Christina Smolke – TRANSCRIPT
Medicines are essential for our quality of life, and yet, we lack safe and effective medicines for many of our most pressing diseases and conditions. Many of these limitations are very closely tied to how we get our medicines. What you’re looking at is digoxin, which is a medicine that’s used to treat heart failure. This medicine is obtained from the foxglove, which is an ornamental plant that is commonly found in gardens. In fact, over half of our medicines are obtained from nature, and a very large fraction of those are obtained from plants. You can imagine that relying on nature to provide our most important medicines comes with many challenges.
The first is that nature is imperfect. These plants take a very long time to grow, oftentimes over the course of a year, and during that time, they’re subjected to variations in weather, to disease and pests, all of which can affect the amount and the quality of medicine that’s available in any given year.
The second is that most of our most valuable and needed medicines are not going to be provided by nature. These plants are not making these compounds as medicines for us; they’re making these compounds for their own purposes, oftentimes for defense, and what that means is that there’s just a large set of medicines that we’re not going to be able to source from nature.
The third is that most of the people on this planet, still to this day, have insufficient access to medicines. With all of these challenges, you might wonder wouldn’t it be better if we could actually just go in and make our own medicines. We took that question and we said, “Okay, let’s start with one of the most complex family of medicines out there”. This is a class of compounds that has evaded decades of research in the laboratory in terms of trying to arrive at better solutions. We said, “Could we develop an approach that’s grounded in biotechnology, that would address a lot of the challenges that arise when we rely on nature to source our medicines?”
What you’re looking at is the opium poppy. It’s from this plant that we get many of our most effective pain medicines. We used this as our starting point. I want to start by discussing the scale of what’s required to source medicines from nature. There’s about 800 tons of opiates that are sourced annually to make our painkillers. What this equates to in terms of land usage is about 100,000 hectares of land that’s farmed for poppies. You can think about this roughly as the size of Rhode Island.
Because poppies require a very specific climate to grow, and also because of the regulation associated with growing these crops, what it means is that there’s a very small number of geographical regions on our planet where poppies are grown. Over half of these come from Australia.
Finally, still to this day, the large majority of people on our planet have insufficient access to pain medicines to treat moderate and severe pain. Let’s look in a little bit closer at what this manufacturing platform actually looks like. There are many steps from the point at which we get or medicinal opioids to the point of the poppy. Essentially, this plant is producing one particular compound, morphine, and it’s making this compound as a very, very small fraction of the overall plant material.
So we have to go into the plant and basically remove this compound so that we can use it as a medicine. That will require us to use fairly toxic chemicals to do that. Because these plants are being grown oftentimes, very far distances from where the medicine is actually being used, we then have to take very large volumes of narcotic material and transport it very long distances to where the medicines will ultimately be used.
Then, finally, because the poppy is not making the most valuable pain medicine, we have to take the compound that we get from poppy – morphine – and then subject it further to chemical processing steps to allow it to be converted into higher value, more effective pain medicines.
The next challenge that arises is that this medicinal plant is not just making opiates; it’s making a number of other compounds that we have great interest in to treat other types of diseases such as cancer and neurodegenerative disorders and hypertension. So we’d like to be able to go into this plant and retrieve these molecules as well. But the plant is making these as a very complex mixture. It’s making all these different compounds together. That adds a lot of cost and complexity in terms of, once we retrieve the compounds, trying to separate them, so that we have purified amounts of each of the compounds that we can then use as medicines and ultimately those challenges will limit our access to those other types of medicines.
Then finally, as many of us are aware of, this type of manufacturing feeds directly into an illegal market, where poppies can be farmed and fed into the heroin market. It’s also the case that we have abuse of these medicinal opioids. We started this journey about ten years ago. We asked a seemingly simple question, which was: could we shift from a manufacturing platform that was based on growing vast amounts of a drug crop, and instead ask a simple single-celled organism, like baker’s yeast, to make compounds that we could use as medicines directly, that would have improved properties.
I want to start with an overview of what this process actually looks like. Again, what we’re essentially trying to do is move from the sort of one organism, one compound that that organism has evolved to make, to one in which we actually go in to the broader natural world and begin to look at the different organisms that are present on our planet and search for activities that we believe would be of interest in making the perfect medicine.
We can begin to look at different organisms, we can pull out activities that we believe will be of interest, and then we can take those activities that are distributed in different organisms throughout nature, and begin to combine them into a new single organism, in this case, baker’s yeast. At the end of that, what we’ll have is an organism that now has these activities combined in ways that you don’t find in nature. We can now grow this organism very inexpensively, and over a period of several days. This organism will be able to provide for us new sets of medicines that we can’t find in nature.
Now that we’ve kind of looked at it at a high level, let’s zoom in to some of the details of what this actually means. At this level, it’s useful to think of the process that’s going on inside the yeast as this really complex molecular assembly line, where this assembly line is essentially taking the sugar that we feed yeast as a building block, and then it’s building it up into a complex medicinal compound that we can then use.
The first challenge that happens is that, in addition to sort of coaxing yeast into making this really complex assembly line, the next challenge we’re confronted with is the fact that oftentimes many of the components that we would like to be able to use to build this assembly line, we simply don’t know what they are; we haven’t found them. This presents us with our first challenge. How do we build within an environment that we just don’t know actually, what we’re asking the yeast to make?
The way that we do this is that we go back into nature and we began to go and search the genomes of those different organisms. Essentially, what we’re doing is we’re looking at the DNA sequences of many different organisms, and that sequence essentially holds the directions for how those organisms make different activities that we believe will be of interest to make new medicines. We can use computational tools that will search those DNA sequences and essentially identify its subsets of the DNA sequence that we believe encodes interesting activities. Once we identify those subsets of sequences, we can simply take that DNA sequence, move it into our yeast host, and begin to test directly whether the activity is actually what we hoped it would be and whether it will work to build our medicine.