Why Bother Being Nice?

The long-term survival rates from pancreatic cancer are notoriously grim. Steve Jobs, Patrick Swayze, Alan Rickman and Luciano Pavarotti are well-known recent victims. The prognosis tends to be so dismal because pancreatic tumours usually come to light only at very advanced stages of the disease, and by then the cancer has often also spread elsewhere in the body. Now Stella Man and Gunnel Hallden, from Queen Mary University of London, have found a way to modify a common cold virus to turn it into a form that can be injected safely into the bloodstream, where it selectively infects and destroys pancreatic cancer cells, including those that have spread to other parts of the body. Starting with Gunnel Hallden, Chris Smith heard how it works...

Gunnel - We have a long experience with developing cold viruses, so called adenovirus, into mutated versions of the virus that can only target and kill cancer cells. Our idea was based on targeting pancreatic cancers specifically; and another advantage with adenovirus - the cold virus - is that they can also sensitise cancer cells to the current chemotherapeutic drugs; so you would kill the cancer cell with the virus. You would also help the chemotherapeutic drugs to kill the cancer cells and then you could also re-activate the immune system, so that was the idea behind this.

Chris - So, Stella, what you were effectively trying to do here is to reprogramme what would be a cold virus and be spread by coughs and sneezes, and make it attack cancer cells. What was your approach to doing that? How did you do that?

Stella - In pancreatic cancer cells they have a protein displayed on the outside of these cells that is not displayed on normal cells. So we took advantage of that and we’ve changed the outer coat of the virus so that this virus can now target the cancer cell and not the normal cells. Another modification is that we’ve engineered the virus so that it can enter the normal cells but it won’t do anything. But when it enters into the cancer cell it can replicate and make more copies of itself, and then the virus bursts out of that cancer cell - killing the cell in the process and go on and infect the neighbouring cells.

Chris - So in essence, we have a virus that seeks our actively cancerous cells of the type that you're going for?

Stella - Yes.

Chris - It only grows actively in those cells and then once it’s grown and increased its number it buds out from the infected cells and infects all of the neighbouring cancerous cells if there are any so, in essence, what it’s doing is it’s growing until it runs out of cancer cells to kill and then it will just stop?

Stella - That’s right; that’s the idea behind it. Which is why we needed to also develop it so that it can be delivered via the bloodstream so that you can reach cancer cells that may have already spread away from its original site of growth.

Chris - And Gunnel, when you do this is it safe to inject this virus? Are you sure that it’s capable of targeting exclusively the cancer cells that you think it’s targeting or is it possible it could get into non-cancerous cells and do harm?

Gunnel - We haven’t obviously tried it in clinical trials yet but when we have done animal studies, and in animals it works exactly as Stella just explained. We can inject it in the blood, it will go to the tumour, it will express its genes and start replicating in the cancer cells, but we haven’t found it in any other tissues in the animals so it seems safe.

Chris- And Stella, one of the key things about cancer is it’s a moving target because it’s a genetically unstable entity and it means that it adapts, it evolves, and it becomes resistant to things like chemotherapy drugs. Is there a way in which the cancers could evolve to duck away from your virus so the virus can no longer attach itself to the cancer and get in via the mechanism that you’re relying on at the moment?

Stella - There’s always a possibility. I guess the length of the animal study is not long enough to see that but we didn’t see anything like that in our animal studies, so we haven’t seen any evidence of that.

Chris - It’s sounds very encouraging doesn’t it? Now given that these are cold viruses - adenoviruses - is there not a possibility that someone has experienced exposure to a virus like this before they could be immune to it and, therefore, that would limit its ability to work?

Gunnel - Yeah. It is possible, especially if you give the virus in the blood stream. But from other studies with similar viruses it seems to be possible for the virus to still reach the tumour the first time. Maybe the second time you would have to modify the virus a little bit but it’s not a major problem. Most of the viruses will reach the tumour.

Chris - What’s the next step them? You’ve proved that you can do this in cultured cells, you’ve proved you can do this in a limited way in animals. Animals don’t naturally get pancreatic cancers like we do so there is an inherent limitation to what you can achieve in animals, is the next step then to go into humans?

Gunnel - The next step would be we would like to first investigate a little bit more about the immune response in animals, and then we would go on and study toxicity in larger animals. After that, we would be ready to apply for funding to go into early stage clinical trials.

Chris - You probably get asked this a lot at dinner parties, both of you, but have you seen the film “I am Legend”?

Gunnel - Oh yes!

Stella - Yes!

Chris - Any reactions to that?

Stella - Those movies look very scary don’t they! It makes it look like a disaster zone so we were actually expecting questions like this but, luckily, this virus is not the same type of virus so it doesn’t carry the same risks!

Who doesn’t like to think of the humble honey bee, buzzing about helpfully pollinating crops and wild plants? Concerns over declines in honeybee populations have resulted in substantial media coverage and a push to up their numbers. But some scientists think that this focus on honey bees could be causing problems for other pollinators. Katie Haylor spoke to one such scientist - Jonas Geldmann from Cambridge University. First, Katie asked why bolstering honey bee populations might mean trouble...

Jonas - Honey bees are, effectively, an agricultural species: we generally have them to produce honey and we have then to pollinate our crops. But when the amount of nectar and pollen from our crops doesn’t match the number of honey bees, they will go and forage in natural habitats in nature all around us, and that can create competition with other pollinator species.

Katie - What kind of other pollinators are we talking about?

Jonas - Primarily bees. But it’s also butterflies, it’s hoverflies that help the natural habitats with the pollination services.

Katie - Do we have an idea of how much responsibility these wild pollinators bear in the terms of the services they provide?

Jonas - I guess there’s two aspects to that: in terms of the actual agriculture where we depend on our honey bees, there are studies that show that as much as 50% of the pollination services could, potentially, be delivered by our wild pollinators, so they could play a major role there. Outside of our crops they could, potentially, be responsible for all of the pollination.

Katie - Okay. So managed honey bees are affecting the resources that are available to these other wild pollinators, is there anything else that we should be concerned about?

Jonas - Honey bees also carry a lot of diseases that they can transmit to wild pollinators simply because they share the same flowers. It’s almost the same as if have a candy bowl on a table that’s sort of equivalent of the flower, and if one person who’s sick eats a bit of candy out of that, the next person who’s going to take some candy is likely to have a higher risk of being sick as well.

Katie - Oh dear. 

Jonas - Yeah. I think it’s important to say this potentially is a problem in some of our very resource poor habitats where most of our threatened pollinators are. The biggest problems to pollinators, both the managed honey bee and the wild pollinators is still intensive agriculture it’s pesticides, it’s this simplification of the landscape that leaves less and less wildflowers around for both the honey bees and the wild pollinators to forage on. But, when that’s the case, there will be areas where the wild pollinators will likely be additionally threatened by the fact that there are honey bees.

Katie - What can we do to address this balance?

Jonas - In the areas where we have set aside land for nature and for biodiversity, we probably shouldn’t have honey bees and this probably includes a buffer. Honey bees can forage as much as 10 kilometres away from their hives, generally less, but they can move that far away so it will likely require a buffer. In the areas where that’s not the case I think there’s a need to assess what the actual need is for honey bees. Right now, because there’s a fairly large disconnect between the farmers who need pollination services and the predominantly hobby type of honey bee keepers, there’s no coordination between what actually is the needs for pollinating services from the honey bees and for the number of honey bees, and this is obviously in space but also in time. Many of these agricultural crops are in bloom for a very short period of the year.

Katie - So a more strategic matching of the number of managed honey bees compared to the wild pollinators.

Jonas - Yes

Chris - What is the comparison when one considers the impact of people keeping a few bees - a few million bees - compared with farmers with intensive agricultural methods, pesticides, other kinds of chemicals that are going on those fields, is it not just kind of David and Goliath?

Jonas - It’s another complicated question. In much of western Europe, the United Kingdom including, biodiversity is in a massive crisis. We’re seeing declines of insects way beyond the pollinators and this is likely largely because of an intensive agriculture that both takes up a huge amount of area where there is growing nothing but one single type of crop, they’re clearing out the areas around the fields and they’re using pesticides that kills almost anything that’s on the field and is likely to have an impact outside of the field. This is obviously across almost any organism the biggest problem for nature. But honey bees are an exceptionally effective pollinator and collector of nectar, so in areas where there are absolutely no agriculture but where there are very pristine nature, very valuable nature, and people are putting these honey bee hives in, they are having an impact on the native wild pollinators and they’re having it for no good reason. So I think it is a place that is still worth exploring even though it’s by no means the biggest challenge to nature in the UK or anywhere else in the world really.

What actually is altruism? Lewis Thomson tells of one remarkable example of this behaviour...

On the 2nd January, 2007, construction worker Wesley Autrey was standing on a subway platform waiting with his two daughters for the train to arrive. Beside them a young man began to have a seizure and fell onto the tracks with a train fast approaching. Autrey realising there wasn’t enough time to pull him up jumped down onto the tracks and lay on top of the man pinning him to the ground to stop him flailing. Amazingly, the train passed over them missing Autrey by just an inch.

This is just one of many examples of instances when an individual has risked their own life to save someone else. And although this may seem like a very human thing to do, altruism - sacrificing something of yours for the good of another individual - is a behaviour found in many species. Individuals will give up their food, breeding rights, even lives to help others survive.

But if evolution is all about the survival of the fittest, how do behaviours like this evolve?

Music: Bensound, drum sfx: Bensound

Does it pay for animals to act altruistically? One species with a particularly strong community-spirit is the meerkat. To find out more about why meerkats help each other out, rather than just fend for themselves, Lewis Thomson and Katie Haylor met up with one human expert, and many excitable meerkats...

Tim - Hello, I’m Tim Clutton-Brock. I’m a zoologist at the University of Cambridge and I work principally on Kalahari Meerkats and we work in a site in the southern Kalahari just on the South African-Botswana border.

Lewis - We’re not in the Kalahari right now. We have come to the Animal Experience in Cambridgeshire and we’re surrounded by about five meerkats I think. They’re all running around. Shall we go in and sit down and get a bit closer to them?

Tim - Fine.

Lewis - They’re climbing over Tim’s shoe at the moment. I’m not sure if he thinks it’s food. No… don’t go for the microphone cable.

Tim - I’ve got a meerkat on me.

Lewis - He wants to be interviewed.

Tim - He wants to smell my mouth too closely I think. The unusual thing about meerkats is that they’re one of the most cooperative animals in the world and for evolutionary biologists cooperation poses a problem. It’s not difficult to understand why animals compete with each other because they’re competing for food and breeding opportunities and so on. But meerkats, like a number of social insects, spend much of their time helping other individuals to breed rather than breeding themselves.

Groups typically consist of one breeding male and one breeding female, and then a variable number of individuals, sometimes 20 or 30 individuals, many of them fully mature who spend a large part of their lives helping to rear offspring born to the breeding female. They enjoy eating people’s ears…

Tim - Eventually the meerkats decided that our producer’s ears weren’t really worth eating. Back to Tim…

Tim - Cooperation on this level is unusual in mammals. Meerkats have a complex system of helping so that when the dominant female is producing pups, other individuals clear out the burrow, and some of the non-breeding females will lactate to the young of the breeding female. When the group leaves the breeding burrow in the morning to go foraging and the breeding female goes with them, one of the helpers will stay and protect the young for the rest of the day with a result that they will spend a full 24 hours without getting any food.

Then once the pups start to move with the group and forage, which they do at about three weeks after they’re born, the members of the group go and collect food and they bring it to the pups. Most of the members of the group give away around half of all the food they find to the pups and they do that for the first three to four months of pup life. When the groups foraging, it’s commonly the case that one individual stops feeding, goes up on raised guard and looks for predators, and gives alarm calls if it sees predators.

Lewis - This raised guard is that classic image of meerkats standing up like footballers defending a free kick. They’re ready to alert their troup to any eagles, snakes, or jackals… So why put their neck on the line like this?

Tim - The only animals that live in cooperative systems like this are animals where all the group members are closely related because most of them in a meerkat group, most of the individuals are full siblings. So they’re helping to rear individuals that are 50% related to them which is the same level of relatedness as their offspring would be if they produced offspring themselves. If their parents are much more likely to be able to produce and rear offspring than they would themselves, another way of breeding, if you like, is to help their parents produce further siblings rather than trying to breed themselves.

Lewis - But why does being closely related, that is having a similar genetic makeup or genotype matter?

Tim - Well, if you put it in the simplest way, animals are selected to maximise the proliferation of their genotype in future generations. So, if you’re helping to rear individuals that are 50% related to you, you’re extending the proliferation of your genotype into future generations just as you are if you breed yourself. If, on the other hand, you’re helping an individual that’s only 5% related to you, you are making very little contribution by that to the proliferation of your genes into future generations.

Lewis - Do you think altruism is an appropriate term to use when we’re talking about meerkat behaviour?

Tim - Well, it all depends what you mean by altruism. These individuals are helping other individuals breed, but that for them is the best way of ensuring the proliferation of their genotype. So there’s a real evolutionary benefit to these individuals, but they certainly are helping other individuals at some cost to themselves so, in the technical sense yes, I call that altruism.

Microorganisms, meerkats, and monkeys - they all behave altruistically for different reasons - but what about us humans? Is there anything unique among us humans when it comes to altruistic behaviour? Katie Haylor spoke to Sander van der Linden, from Cambridge University....

Sander - I think when it comes to human altruism there is a defining feature. Whereas in biology it’s about increasing the fitness of an organism at the expense of your own fitness, so your own potential to reproduce genetically. With humans it’s all about psychological motivations that we have to disentangle, so what are the motivations for helping someone else? And I think that poses a fundamental problem to try and figure out how altruistic we are exactly in different situations.

Katie - How do we explain the random acts of kindness, the good samaritan? Say Wesley Autrey we heard about before who dived in front of a train to help that person he didn’t know, how do we explain that?

Sander - Yeah, that’s a great question. We’ve heard about kin selection: sometimes we help other people because they’re just genetically related. We’ve heard about reciprocal altruism: scratch my back, I’ll scratch yours. But what about those cases where you’re not going to interact with a stranger ever again, why would you be incentivised to help that person?

I’d like to split that out into two motives: an individual motive which is that a lot of research shows that people derive positive internal benefits when helping other people. When we help other people the heart rate tends to go down, our blood pressure tends to go down and it can have positive impacts on depression. When you put people in neuroimaging scans it shows that the reward centre of the brain lights up in certain situations. Economists refer to this as ‘warm glow,’ and so the idea is that people derive pleasant emotional experiences from helping other people.

The other is more social that we care as a group-living species we care about our image. You see this in primates too, but especially in humans we care about our reputation. We want to be seen as a cooperative individual who’s going to help and benefit the group. That we’re going to essentially do our bit because that’s an adaptive advantage to have as a group member. This is called image motivation.

Chris - Is this inherited or learned?

Sander - Another great question. We learn about norms in our societies. To some extent this evolves but, on a more simpler level, we acquire norms through social learning. If it’s the norm to help other people, we learn that from other people. Sometimes norms are institutionalised and they get passed over from decade to decade, and even if you talk about cultural evolution over larger time periods. but there’s a lot of variation in culture. The extent to which culture replicates like a gene is a bit more complex but, certainly, we inherit rules and rules of thumb and norms from observing other people.

Katie - This notion of it feels good to do good deeds, does the dopamine reward system come into play here?

Sander - Yeah. Some studies show dopaminergic pathways are activated when people think about donating, for example, or helping other people, and so these ‘feel good’ neurotransmitters are released. Sometimes it’s a bit difficult to disentangle because there’s always other factors that can activate similar neural substrates, and so it’s always a bit difficult to tease out causality but, generally, those factors are associated with helping other people.

Katie - Could the notion of being nice to strangers, could this idea have evolved as a byproduct of it being beneficial to be nice to your friends or your peer group?

Sander - I think it’s difficult to tease out basic mechanisms such as the ability to experience pleasure which is not necessarily related to altruism, even though those mechanisms are associated with, for example, helping other people. Those mechanisms didn’t  necessarily evolve solely for that purpose. I think that is difficult to say but, generally, helping other people is adaptive. In a group-living species it’s extremely adaptive if groups are able to cooperate because then they can outperform groups that don’t cooperate, so the fact that these behaviours are adaptive to some extent. I’d like to think, at least, that people on some level recognise that helping other people is adaptive and that that is the reason why it makes us feel good in the end. But, of course, the ultimate answer to that remains somewhat of a mystery.

Katie - If helping others makes us feel good, is there such a thing as a good deed if we’re getting something from it?

Sander - This is one of the questions I always ask my students because this is essentially a game. I can reduce any behaviour to an egoistic motive. If it makes you feel good it disqualifies as true pure altruism. So if you jump in front of a train to help somebody else, if you experience the slightest amount of ‘warm glow’ in that act theoretically it could disqualify as pure altruism. But I think that’s not the key factor because it seems that it would be unrealistic for us to be so altruistic all of the time. I think if we help other people and we feel good about it and there’s a mutual benefit, maybe we should be satisfied with that.