Translator: Barbara Lapico Reviewer: Reiko Bovee
These are tobacco plants, regarded by many
as one of the most lethal killers of the 20th century.
But what I want to tell you about today
is how possibly through the use of modern biotechnology,
we could turn this plant around from a global killer to a global healer,
to use tobacco plants to manufacture medicines,
and to address some of the major global issues
that we fail to face in health around the world today.
Now, here in the UK and elsewhere in the developed world, of course,
we have access to a huge plethora of medicines and medications
against almost every conceivable disease.
Some of them more useful than others, of course.
But if you go global, the stark fact of the matter is
that something like 30 to 50 percent of the world's population
don't have access to essential medicines,
by which I mean antibiotics, normal medicines for normal diseases,
that kind of diseases they get, and vaccines.
So, I think a fundamental question we face for the future is:
How do we start to make medicines available
for the poor in developing countries, who cannot afford to pay for them?
Well, about 20 years ago,
a group of scientists started thinking about whether we could use plants
to answer some of these questions.
Of course we've always used plants to make medications,
but this is not the same kind of thing.
What we're using here is applying the new technology of genetic engineering,
to engineer plants, insert fragments of DNA to ask them
to manufacture the medicines specifically that we want to.
And we call this field molecular farming,
and we regard it as an unprecedented opportunity
to make modern medicines economically,
and at a scale that is relevant for global health.
Now, you can make all sorts of medicines using this kind of technology,
but what I want to focus on today are these proteins called antibodies.
So, antibodies are the proteins that our white blood cells normally make
in response to infections and other diseases,
and they are largely responsible for us getting over our infections
and prevention of future infections.
Now, the pharmaceutical industry has already been quite successful
in making synthetic antibodies outside of the body.
You may have heard some of this, like Herceptin,
which is used for treatment of some breast cancers.
So, the antibodies we have at the moment, there are only a few of them,
are currently very successfully used in the treatment of diseases like cancer,
some infectious diseases, and chronic illnesses, like rheumatoid arthritis.
The problem is that they're really very expensive,
and this picture gives you some ideas of why.
This is how the pharmaceutical industry makes these antibodies at the moment.
In the bottom left of the picture
is a picture of some ovary cells from a Chinese hamster.
And these cells are genetically engineered to produce the antibody molecules
and they are growing up in these large stainless steel fermenters or vats.
When you look at this picture, which is of a pharmaceutical production facility,
you can see that it's very well controlled,
it's pretty clean, probably sterile, and, like that famous lager,
reassuringly expensive.
So, how would we do that in plants?
How would we do something similar in plants?
Well, actually we rely on this little bacterium, Agrobacterium tumefaciens,
and the gardeners amongst you may well be familiar with this bacterium.
It's commonly found in the soil,
and it causes this disease in the bottom left panel, called crown gall disease,
which you commonly see on rose bushes and fruit trees.
And it does this by attaching to the plant cell,
and injecting a small amount of its own DNA,
which goes into the plant cell, and transforms the DNA
within the nucleus of the plant cell,
and essentially becomes integrated into the plant DNA.
Now back in the '80s,
what was realized is that you could disarm Agrobacterium,
remove those genes that insert into the plant cell,
but replace them with your genes of interest.
So, in our case, those would be the genes, the DNA
that would encode for the antibodies that we want to produce.
So, this is what a plant manufacturing facility would look like,
and, in fact, it does look like.
This is a photograph taken from my friend and collaborator's laboratory
in Germany, at the Fraunhofer Institute,
and this actually is a production crop of tobacco plants
that we used to make antibodies.
But spot the difference from that stainless steel fermenter picture
I showed you earlier.
It's not as clean, there's no doubt about that, it's not as well controlled.
But, because of that, I think,
the pharmaceutical industry and the government regulators,
who've controlled on new drugs have concerns
whether we could make antibodies of the same quality
that they've made from CHO cells.
But then, also think about the advantages.
This is clearly a much cheaper investment to make,
and the scalability is really limited only by the scale
of the greenhouse travel available to you,
not by the size of that stainless steel fermenter.
So, to address this concern about whether plants could be used
to make high-quality antibodies that would match the ones
that we already have available;
in other words, pharmaceutical grade antibodies.
In the 2000s, we and a number of laboratories around Europe
were funded by the EU to ask that specific question.
And I'm not going to bore you with the details of this 8-year project
because it's a very large piece of work.
But I will tell you, at the end of it, we did achieve it;
we achieved it to the extent that we persuaded government regulators
that the process that we used to make our antibodies in plants,
and the final product was at least as good, if not better than the product
that could be made in the Chinese hamster ovary cells in stainless steel.
And, because of that, they granted us a license
to manufacture antibodies in plants,
and they also allowed us to move this into a human clinical trial.
And I can tell you today that that antibody we produced is safe,
and this opens up a huge number of doors for future projects.
So, what kinds of applications would be like to use these antibodies for?
Well, our primary interest has always been in HIV,
developing country, predominantly developing country diseases,
mainly in Sub-Saharan Africa.
And our concept is to produce antibodies in plants and formulate them [into a gel]
[that should] be applied in the vagina before sexual intercourse
to prevent infection by the virus.
So you can see in the bottom left-hand panel here such a gel;
it's called microbicide, microbicide gel.
And this is the kind of applicator that we use.
And the idea is that the woman would insert the gel before sexual intercourse,
and [if] it encounters the virus,
the antibodies in the virus would kill it, kill the virus
before the virus had the chance to enter into the woman's circulation.
I like to think of this as a biological condom
because it acts as a barrier to HIV infection.
But It needs to be readily available, and it needs to be really cheap.
It can't come at too high cost, that would put people off from using it.
Unlike a condom though, it has a couple of other advantages.
It empowers women to take control of the prevention of HIV for themselves,
and it also allows women to get pregnant whilst protecting themselves against HIV,
which is a very important problem.
There are other areas in HIV to use antibodies for.
We're particularly interested in this field
of preventing mother to child transmission.
So this would be HIV positive women
and trying to stop the transmission of HIV
to their unborn child or perhaps their child during delivery.
Of course we do have antiretroviral drugs,
which are currently used for this purpose and are actually very effective.
But the problems is, the closer you get to the term to the birth of the child
before starting these antiretrovirals, the less effective they become.
Now, we already know that you could use antibodies in pregnant women.
We use those for other reasons.
So, we just extend this idea,
and we are looking at the idea of using HIV antibodies
in late presenting pregnant women with HIV to protect that child at child birth.
We are not only interested in HIV.
Rabies has been a long standing interest in my lab at St. Georges,
and, over the last 20 years,
we've been trying to develop also antibodies to prevent rabies.
So, rabies is still a big problem in South-East Asia,
and all over Africa, actually.
And, although we have a really good vaccine against rabies,
it's just far too expensive to supply to the whole population.
So, the standard of care in these places is to wait for somebody to get bitten
by a potentially rabid animal, often a dog and therefore often children,
to take them to a local clinical hospital and vaccinate them,
if the vaccine is available.
But also, the key component of that care is to give them a product,
rabies immunoglobulin, which is essentially antibodies against rabies
which had been developed in either horses or humans.
Again, there is a problem.
Those antibodies are really expensive, and many times,
particularly in South-East Asia, they're just not given.
So we think making a cheaper source of antibodies, more readily available,
would make a real impact on the control of rabies in developing countries.
The fourth and last example
I'd like to give you of plant antibodies preventing diseases
is one that may well be known to many of you,
and you'll remember last year the outbreak of ebola infections in West Africa.
Now, it comes with no surprise to you,
because this is certainly a developing country disease:
There was no vaccine, no treatments available for ebola.
So, when people went out to help in Sierra Leone or Liberia,
like this guy, William Pooley, a NHS nurse,
and got infected and became ill,
when they came back, there was very few options for treatment.
William Pooley was fortunate, because at that time,
there was an experimental drug available, called ZMapp, and he was given this drug.
So, ZMapp turns out to be a cocktail of three antibodies against ebola,
that were made in tobacco plants by a small american company.
And, in this case, there appeared to be a very rapid and surprising recovery.
He was one of nine patients treated with ZMapp; six of them survived.
And this's given them a great hope that these kinds of antibodies
could make a big difference next time there's an outbreak of ebola.
And so, for that reason, the US government
has put a lot of money into the development of this product.
What they want to do is go into the clinical trials
that will formally demonstrate
that ebola antibodies ZMapp work and are safe,
but also to start stockpiling for the next outbreak.
And I want to just give you some idea
of what stockpiling or scalability in a plant expression system looks like.
So, I'm very grateful to a company called Kentucky BioProcessing,
who is manufacturing ZMapp, for sending me this picture.
This is a warehouse they have in Kentucky,
where they're growing thousands of plants to produce ZMapp antibodies.
And you can see this is not an expensive outfit.
This is essentially just a growth, a growth chamber,
just happens to be a very large one.
But I would argue you that this is the only way
that we are going to start making antibodies
against these truly developing country diseases
which many other countries, particularly in the developed world, have no interest.
So, through these examples
I hope I have drawn you into our vision of a new future for tobacco:
Changing this plant from a global killer to a global healer,
using tobacco as a plant in the manufacturing sense of the term
for modern medicines.
And the image in this last slide of mine really makes the final point,
because however cleaver your technology is,
you're never going to solve the world's problems
from our laboratory or even a factory in the developed world.
You've got to engage and work with people in developing countries,
where the problems are.
So, this picture shows you that tobacco is, of course, a global crop.
There is expertise and technology for growing tobacco all over the world.
So this gives us a great opportunity to transfer some modern technology,
to build industries in the developing, underdeveloped world, developing countries
to start making medicines
which are appropriate for the diseases in that area.
That's a concept
that we call manufacturing in the region for the region.
Thank you very much for your attention.
(Applause)