Inside Every Human Cell May Lie the Fountain of Youth

Professor Douglas Melton introduces the astounding advances being made today to unlock the powerful potential hidden within our own cells.

I’m Doug Melton; I’m the Thomas Dudley Cabot Professor of Natural Sciences at Harvard University, and the Co-Director of the Harvard Stem Cell Institute.   

Well, I’m glad to talk to you today about an exciting new biology in medicine.  It’s what I call the biology of regenerative medicine and it’s going to change your life.  It’s going to lead to longer and healthier lives for humans in a way that was really unimaginable just a few decades ago.   

Let me put this in perspective.  In the last century, infectious disease caused enormous suffering and harm to many millions of people.  A simple infection like whooping cough or diphtheria or any kind of bacterial infection, led to millions of lost lives and suffering until the discovery of antibiotics.  Once antibiotics were discovered, what now, for today is a simple infection would cause death.  And now today with an antibiotic, we can eliminate that.   

I’m going to talk to you about a biology that will similarly change our lives.  It’s a biology based in stem cells and genetics and it has to do with understanding with how our bodies are made, maintained and replenished, and it will also teach us something deeply important about disease.  Most interestingly perhaps, it will also open the door to manipulating our bodies in a way that we can change who we are and what our lives are like.   

To put this in a little more perspective, let me remind you that in the last century, beginning with Mendel’s discovery of genes and genetic inheritance, we learned about the genes we inherit from our mother and father affect who we are.  That was reduced to understand that genes are made of DNA, the chemical stuff of genes is DNA.  And we now understand quite a bit about how genes encode the proteins that are found in our body.  It however, can be an exaggeration, often appearing in the popular press that all we are is our DNA, and we’re much more than our DNA.  Our DNA is merely a language or a code that tells our body or our cells what kind of proteins can be made, but the DNA doesn’t define who we are.   

So what has been lost in this discussion up until now, is the idea that the real unit of biology is not DNA, but is instead a cell.  Cells are alive, cells make more cells and cells are the units that allow us to harness the future of our bodies and regenerative medicine.   
So let me move to this point by saying that I think in the 21st century, biology will usher in advances in regenerative medicine and stem cells will be at the center of discovery and application in that new field.  In order to make sense of this, we have to dig into a little bit of a kind of biology called Developmental Biology.  That’s the biology as shown here that has to do with answering a question, how does an egg become a human being?  How does an egg make a human body?   

In the last century there were two important advances in biomedicine.  One was the discovery of antibiotics, which made it possible to then cure people of these what we consider to be common bacterial infections and led to so much disease and suffering.   
The second major finding of the last century was an understanding of genes.  This began with Mendel’s working on peas and understanding that our parents each give us some units of genetic inheritance which came to be known as genes.  That led then to the finding that genes are made of DNA and that was concluded at the end of the last century with the decoding of all of the DNA, the sequence of the entire human genome.   

But this, we should remember, is sort of like learning the letters of the alphabet or the words involved in a language.  And language and books are much more than the letters of the alphabet or the words, it’s the way they’re combined.  And that combination, to make the analogy with biology, occurs in cells.  Therefore cells are really the units of life.  Cells are alive, cells make more cells and it is cell biology that is going to change our understanding of our bodies and lead to new understandings of disease and development.   
Let me explain that a bit more.  I’m going to make the case that in this century, the 21st century, biology will usher in advances in regenerative medicine.  Stem cells will be at the center of this discovery and application.  To make sense of this, let’s remind ourselves what happens during normal human development.  It is a great mystery and puzzle of how an egg becomes a human body.  I’m going to show you some pictures of how this happens and talk a bit about the very early stages of human life.   

In this picture here, you see the first spark that starts human development, that is fertilization.  You see a large yellow egg there, a human egg, with many sperm trying to fertilize it.  Only one sperm wins, one of those blue-headed sperm and that then leads to the first step, which will be cell division.    

Cell division occurs rapidly over the first few days of development and as you see in this picture, there are two cells that are formed from the fertilized egg.  Development proceeds a pace and forms an early stage of development called the blastocyst.  This is quite an important stage and I’ll come back to it later, but the portion of this picture in the upper left is called the inner cell mass, and the few cells there out of the 100 cells at the blastocyst stage, it’s those few cells in the upper left that will give rise to the human body.   
Within a few hours, development proceeds quite quickly and we can see here by one month later, the basic body form is already apparent.  One can see the beginning of arms and legs, the heart, the eye and the facial cavities are starting to form.  It’s just a short time after that, at 46 days, when it’s obvious then that an embryo is already formed.  There’s an arm and a leg and you can see a kind of a cavity at the top in this picture where the brain isn’t fully formed, brain cells are being made, but they’re not completely developed yet.   

To conclude then, by 70 days, you see something that’s clearly human.  So within just 70 days, one has gone from a fertilized egg to something that’s clearly human, not yet fully developed, but clearly human.  For me, this is one of the most mysterious and wondrous things about biology.  How does that fertilized egg make this human in just 70 days?   

Now, it’s not a human being yet, but it’s clearly on its way to being a human.  And I like to sort of contrast this with things that we’re commonly amazed by in our life.  Things like an iPod or a computer are not nearly as wondrous to me as how this fertilized egg made all of these body parts in just 70 days.   
Well to look at that in a little bit more detail, let’s consider this picture where there are two aspects to human development.  The first is obvious, is growth.  Cells not only divide, but they have to increase in size and then growth occurs inside the womb of the mother.  But the second and the one we’ll focus on today is a process called “differentiation” where cells become different from one another.  

Here you see in the bottom of this picture, arrows pointing to the fact that different cells of the early embryo will give rise to different kinds of cells in the adult.  The blue cells are representing nerve, the red cells there in the middle are blood cells and at the bottom is an organ, the pancreas, which makes insulin so that we can make use of our food.  That process of “differentiation” proceeds until we make all of the different kinds of cells in the human body.   

This picture shows, on the right, a fully formed cartoon of a human.  It’s estimated that there are about 350 different kinds of cells in the human body.  And as you see then, the puzzle is, how do these cells arise from a single fertilized egg?   

In the last century, we’ve learned quite a bit about that.  The first thing we know is that there are approximately 25,000 human genes, bits of DNA that code for proteins, that make up all of the proteins found in our cells.  Now the puzzle then for a developmental biologist is to figure out how do those 25,000 genes get mixed and matched to make all the different kinds of cells?   
We don’t understand that in detail yet, but that’s an exciting and important problem for the next generation of biologists.  How do you take 25,000 genes and make all the different cells in the body?  I sometimes think an interesting analogy for that is, when you go to a Chinese restaurant you can often see hundreds of dishes on the menu, but if you’re in the kitchen, you might only find 10 or 12 different pots.  It’s the way things are mixed and matched that makes the different meals.  Similarly, it’s the way our gene expression is mixed and matched at different times and amounts that makes all the different kinds of cells in our body.  

Now, an important point discovered just in the last few decades is that while cells become different, they are differentiated as shown in this picture.  They retain the capacity to do everything else.  This is quite an amazing potential and it was demonstrated or identified by an important experiment called cloning.   Many of you will have heard about cloning and I’m going to explain that to you in a bit of detail now because it establishes the very important principle that all of the cells in our body have this enormous potential locked inside of them.  

Cloning

This next picture then shows the result of the first cloned animal.  On the right, you see 30 cloned adult frogs.  These are genetically identical; it’s as if they are twins many times over.  They were prepared from a mating of the two albino or white frogs shown in the middle part of the picture.  And in that part of the picture, those two, a male and a female frog were mated to make an albino frog.  And then nuclei were taken from that and injected into the egg of the donor shown on the left.  That’s a wild type, or a normal frog.  And that then gave rise, as I said, to this cloned animal, 30 times over.  One could do this again and again and make many animals by this cloning procedure.   

Let’s have a look in a little more detail with a cartoon of how that’s actually done because it’s an important experiment showing how one can reveal the potential of all of the genes in our cells.  In this little cartoon movie, you’ll see a pipette and remove the nucleus that contains all of the genes from this… from the egg cell.  So here comes the pipette, removing the nucleus leaving just the cytoplasm of the cell.  The picture now shows taking the nucleus from a skin cell and injecting that into the egg cell.  That sparks development, it goes on to proceed as shown in this cartoon where the nucleus is not receiving signals from the cytoplasm as to which genes should be turned on and off and development will proceed by cell division, it’ll then give rise to the blastocyst stage that I mentioned earlier.  And you see in this picture the blue cells will appear shortly, those are the cells of the inner cell mass that will give rise to the whole embryo.  So that’s the blue cells there at the top.   

I thought it would be nice to see what does this look like in real life.  So now I have a real life movie of a cloning experiment we’ve done with mice.  It’s the same procedure, but in real life.   

Here you see on the left, a holding pipette, which just provides a little suction to hold onto the egg.  The egg is inside and the injection pipette on the right has to penetrate a membrane.  That membrane looks sort of like the rings around Saturn.  That egg has got this protective membrane and the pipette is drilling a little hole in there.  It’s now drilled the hole and has removed the nucleus from the egg.  You can see the nucleus is that sausage-shaped thing inside the pipette, which is going to be spit out.   

So now we have the cytoplasm, which is the recipient for the cloning experiment.  We’ll get that one out of the way.  And now I’ll show in the next part of this picture a new egg coming in which has been nucleated, and now we’re going to inject a nucleus from a skin cell into that egg.  Here again, it’s held with the holding pipette.  The injection pipette drills a little hole through the membrane, spits out the unwanted stuff, and then watch as this sausage-shaped nucleus come in from the right.  The pipette’s going to be pushed deep into the cytoplasm and squirt the nucleus into that egg.   

We’ll do that again.  We can line these up like a factor and do them one at a time and you can to tens of these at once and then reimplant the injected egg into a mouse to give rise to the cloned animal.   

Now it looks relatively easy here.  It’s not something you could do at home, but with practice, you can become quite an expert at this cloning procedure.  As a result of that, at least one famous clone has been made, that’s the famous sheep, Dolly.  You see here in the next picture, a picture of Dolly and her surrogate mother, the injected egg was put inside of the uterus of the sheep on the right, the black-headed sheep.  And then Dolly, on the left, was born as you see here in this picture.   

After that finding, it’s been possible to clone a number of kinds of animals.  Here you see Dolly up on the top left in the picture, a horse cloned on the right, a dog on the bottom left, on the bottom right is a whole set of clones obtained from one cow.  You might ask yourself, why would you close cows?  Well, the answer to that is some cows are very good at milk production, can makes tens of gallons of milk a day, and rather than trying to breed them naturally to get more and more cows with an enormous capacity for milk production, one can clone them and then immediately in one generation get a whole herd of cows that are good at milk production.   

So in this point of our understanding, scientists have been able now to clone quite a large number of animals.  Shown in this picture is a list of those cloned recently:  sheep, cow, goats, pigs, rabbits, horses, ferrets.  I know of also common pets, cats and dogs. 
 What’s missing from this list is humans.  I believe it’s possible to clone humans.  It hasn’t been done, but that’s something we should think about and discuss is what would be the value on cloning humans and whether or not our society should allow that to occur.   
For a biologist, however, cloning humans is not the interesting challenge.  We’ve already learned what we want from the cloning experiment and that’s summarized here.  What we can conclude from cloning is the following:  the nucleus of the cells of your body, many, if not all, of the differentiated cells in your body can be reprogram by egg cytoplasm so that they can become fully potent stem cells and make an entire new animal.  Another way of saying that is that during development from a fertilized egg to an adult human, there are no irreversible changes to the genes altogether called our genome during development.   

So what I’d like you to remember from this is that many cells in your body have this astounding potential.  They have locked in their nucleus the capacity to make any other part of your body.  Regenerative medicine is all about harnessing that potential to make new cells and to treat and cure diseases.   

Let’s go now to this problem of cell differentiation.  We’re obviously not going to begin cloning people to make more cell types.  What we have to do is make use of the conclusion from cloning to understand how we can harness and manipulate our own cells.  That has to do with this issue of cell differentiation.  So as I’ve said and is shown again in this picture, cells become different during development, but they don’t permanently lose the information that allows them to make any other kind of cell.   

How might we get at that?  Well the reason we want to get at it, of course, is if we could do that, we could replace damaged or diseased body parts.  If one’s in an accident and loses some tissue or an organ or as is more common, suffering from a disease, a liver disease or a heart disease or a disease of the skin, one should be able to use our bodies own inherent capacity for development to replace or repair those lost tissues.  

Regeneration

Now our bodies, as you may know, have the capacity to do some replenishment on their own.  Not all parts of our body, but some of them are constantly replenished.  You probably know, as shown here in this picture, that your skins turns over and is constantly renewed.  When you got up in the mirror… or when you got up this morning and looked in the mirror, you of course recognized yourself, but if you were looking at the level of individual skin cells on your face, you’re looking at a completely new person, a person that wasn’t there three months ago.  And that’s because our skin is sloughed off and new skin cells come back again and again.   

That’s also true for our intestine, that is, our gut.  Our gut cells are sloughed off at a very rapid rate and are constantly being repaired and replaced.  So our body has the capacity to renew and replenish some of our tissues, but clearly, we don’t have an obvious capacity for major organ replacement.  If you were to lose part of your brain or to lose a limb, your body doesn’t have the capacity to replenish or replace that.  And yet I’ve told you that our cells have all that information inside.  So this raises the challenge or the prospect of how could we learn about cell biology to do real regeneration or replacement?   

So let me now talk a bit about regeneration.  What is regeneration and what do we mean by it?  This picture here is a painting from Rubens of a Greek myth.  Zeus punished Prometheus for giving fire to humans.  And as you see in this picture, they’ve chained Prometheus to a rock and then sent an Eagle to peck away at Prometheus’ liver every day.  Well, it turns out; probably the only organ other than skin that our bodies are good at regenerating is the liver.  So lucky for Prometheus that the Eagle was only interested at pecking at the liver.  If it had been eating other organs, like his heart, he’d have been a goner.   

We want to therefore understand really this process of regeneration, as I’ve said.  Why is it that the liver can regenerate and other tissues don’t?  So regeneration then is the reactivation of the normal process of development and we would like to use it to restore missing or damaged tissues.   

Now as I’ve indicated and as you know, we as humans aren’t very good at regeneration.  But there is one vertebrate, one animal with a backbone, which is extremely good at regeneration.  It’s what I would call, the kind of regeneration, an expert.  And here’s a picture of this species.  These are salamanders.  Common salamanders found in ponds all across the United States.  These animals can do an enormous feat of regeneration.  They can regenerate their tail.  They can regenerate their limbs, their lower jaw and some of their internal organs.  And I thought I’d show you a movie here, a cartoon of what we know about this and how it works.   

So in this picture here, you’re going to see a cartoon of the normal process of regeneration sped up by time lapse photography.  So here, a limb had been amputated and you see taking pictures every few days, a new limb growing back.  Now a cartoon of what this looks like is shown here, and if you are a little queasy, you can avert your eyes when a little scissor comes into this cartoon.  What we’re going to do is cut off the limb; here comes our scissors to remove it.  That leads to a little bit of bleeding, the bleeding stops, that’s the worst part.  And now a special skin, called the “wound epidermis” grows over the stump and now inside, a quite amazing process takes place.   

You can see here, the bone in white and the muscle in red is starting to be changed to dedifferentiate, to become unspecialized, and create a mound of cells that will then go on to grow and recapitulate or reproduce a normal process of development.  That takes a couple of months’ time.  New cartilage and bone forms, there’s a new radius and ulna and all the carpels and the digits of the hand.  So now our happy little Salamander has his limb back and he’s ready to go back and swim in the pond.   

In real life, the time lapse pictures shown here in still form, shows that if one cuts through the upper arm, through the radius and ulna, or cuts here through the humerus, one can see that in both cases, by 70 days, the animal has regenerated its entire limbs.  

The point I’d like to make here is that vertebrate animals have in their cells, the capacity to make any new part of their body and Salamanders have figured out how to do this on a large scale.  A great challenge for us now is to figure out how we could learn to harness those processes to use them in human biology.   

If we look forward to how that’s going to be done, it is, as I’ve indicated already, going to begin with learning about cell turnover.  And that leads us to a very special kind of cell called a stem cell.  I’ve already mentioned that cells in your body are not static, that they turn over.  This picture here shows that our intestinal cells last a few days; blood cells last up to about 10 weeks and you sort of already know that because you may have donated blood at a blood drive.  When you go to a blood drive, you are not permanently in deficit for the blood you donated, but your body tops up and makes new blood.  The pancreas cells on the other hand, cells that are important for digestion and the use of food, live for months.  Not as little as ten weeks, but for a much longer time.  And your brain cells are nearly permanent.  They don’t really turn over at any appreciable rate.   

Well, what’s responsible for this turn over?  How are these cells replenished?  There are two ways our body does that.  This slide shows that it’s done either with a stem cell or let’s look at the bottom of this picture at the division of fully differentiated cells.   
In the bottom picture, let’s imagine a pancreas or a kidney cell which just divides to give rise to two more kidney cells.  The top is really what I want to focus on today, which is a stem cell.  These cells are very unusual because they have the capacity to make more of themselves, to self-renew, and to give rise to daughter cells that are fully differentiated.  

So how our cells in out body are replenished.  There are two ways this is done.  One way is for a fully specialized differentiated cell to just divide and make two.  That happens for cells in our pancreas and in the kidney, for example.  But for many tissues in our body, there’s a special cell called a “stem cell.”  That cell has two interesting properties.  One is, it can make more of itself and the second important one is that some of the daughter cells can become specialized and do different things.  A stem cell then has these two essential properties; self-renewal and the capacity to make specialized cells.   

I want to focus a bit on this first one of self-renewal.  I’ve been talking about how we renew our bodies, well, this stem cell does that on its own, that is one cell can make more of itself.   

If we can understand how a stem cell makes more of itself that should deeply inform our thinking about how we can renew, not only a cell, but tissues and organs.  So we’re very keen to understand this process of self-renewal.   

A second thing a stem cell can do is make specialized or differentiated cells.  Probably the best known of these is a bone marrow stem cell, a blood stem cell, which is given to cancer victims.  And this cell makes all of the tissues of the blood, all of the… the picture here showing all the different kinds of blood cells.   

Now among stem cells, there’s my favorite one, the one that has truly special abilities and that’s called an embryonic stem cell.  An embryonic stem cell can not only self-renew like all other stem cells, but its special capacity is to make all different kinds of cells.  Indeed, it can make blood, it can make nerve, it can make the whole pancreatic islet, the part of the part of the pancreas that makes the hormone insulin.  So if one thinks about the significance of that, that means the discovery in the last couple of decades of stem cells has provided us with a reagent, a tool that can make any tissue in the body.  It can make all of the skin, brain and nerve, what’s called the ectoderm of the body, the outside of our body.  It can make all of the tissues on the inside, the mesoderm, which includes blood, heart, kidney, muscle and bone.  And it can make the gut tube, the endoderm, the lung, the liver, the stomach, the pancreas, the intestine.   

So to emphasize this, I want to show you a movie, something we do with students in the lab where we take human embryonic stem cells that are growing in a dish and turn them into beating heart cells.  So a petri dish has a colony or clones of these human embryonic stem cells growing.  And the arrow shows they are under self-renewing conditions.  When those conditions are removed, the cells automatically begin to specialize.  Here there’s red, yellow, blue, and purple cells, but the ones I want to show you in the movie are human heart cells.    

A striking example of human embryonic stem cells becoming a particular kind of cell is presented with a very simple experiment.  Here we have human embryonic stem cells growing in a petri dish as colonies.  If we remove the conditions that allow them to self-renew, removing that arrow, they will begin to automatically specialize and you can see here, it’s demonstrated or indicated by red, yellow, blue and purple cells.  But I wanted to highlight one particular kind of cell that can form here, which is human heart cells.   
The movie shows these cells beating.  They’re a little tiny clump of cells beating just like a heart.  Here are four different examples of it.  It might remind you of Edgar Allen Poe’s story, The Telltale Heart, where he couldn’t stop the heart from beating under the floorboards.  Here, once we take these human ES cells, as we call them, in a dish making heart cells, they’ll beat for ever and ever.  Now, the trouble here is, we’re not making a heart.  I want to emphasize that we are making a tiny little clump of cells.  And so biologists have been thinking about, how could we use those beating human heart cells to actually make a real heart.   

Well, this picture shows the way we might go about doing that.  In this case, we’re taking a rodent, a rat heart, and removing all of the cells, leaving a kind of a ghost.  You see here the white ghost on the right, which is a de-cellularized rat heart.  So it just has the matrix, the kind of scaffolding for a heart, but there aren’t any beating cells there and it’s dead tissue.  We can seed that scaffold with human or mouse embryonic stem cells that have been turned into heart progenitors.  And they will go on then to form a beating heart.  Here you see this heart pumping away which has heart cells that are made from embryonic stem cells.  That’s the sort of the beginning of a field called bioengineering where we’re thinking about how we would make organs and then eventually, of course, transplant them into people.   

Now one thing I’ve skipped over here is, where do these especially interesting and important embryonic stem cells come from?  Where do we get human embryonic stem cells?  Let me show you that those are derived from a sort of complicated procedure making use of material from in vitro fertilization clinics.  So as you probably know, some couples who want to have a baby are unable to do so by what we would call natural means.  They go to their doctor at the IVF clinic, In vitro Fertilization Clinic, and donate an egg and a sperm, which is then fertilized in vitro.  If that’s successful, some of those fertilized eggs are reimplanted into a woman and then after nine months, a baby is born.  No matter what happens at the end of that procedure, if there is a baby and it’s successful or not, there are almost always leftover human fertilized eggs.   

It’s estimated that there are about 400,000 such eggs in freezers in the United States.  My colleagues and I use those to derive human embryonic stem cells.  We derive them from fully informed consent, where the sperm and egg donor have said that rather than throw that material away; why not use it to try to find more about human development and disease.   

So what you see is that we can take a human fertilized egg, allow it to develop to the blastocyst stage, which I’d mentioned before, in a petri dish, and then from the inside of that, culture out and derive human embryonic stem cells. The inner cell mass of this culture blastocyst is removed and put in a petri dish and then after some weeks of growing, we can isolate human embryonic stem cell colonies from it.  A real life picture of that shows a blastocyst with its inner cell mass on the left and then the colonies of embryonic stem cells derived on the right.  And over the last decade, we’ve gotten quite good at this and now we can isolate human embryonic stem cells with about a 50 percent efficiency.   

It is worth noting that this has raised ethical questions which have important political implications and something for further discussion.  Nonetheless, I believe that it’s perfectly justified, in fact, it’s something we should certainly do to try to alleviate human suffering by making use of this material which would otherwise be thrown away, to try to find treatments and cures for human disease.   

I’m glad to say that in recent years there’s been another possibility of creating a human stem cell, what we call a pluripotent stem cell, which has many, but not exactly all of the properties of the human embryonic stem cell.  And this one doesn’t have the ethical complications of beginning with a human fertilized egg.  This method is to take a portion of skin, a skin biopsy, and then to add DNA or RNA genes that encode reprogramming factors to these skin cells.  And we can make a patient-specific stem cell, shown here in multiple colors because of a florescent image, which is very similar, though not exactly identical to a human embryonic stem cell.   
In the next few years, we may be able to find ways of turning these into a fully potent cell, just like a human embryonic stem cell.  And that would be wonderful because it would then remove the need for dealing with these human fertilized eggs.   

Well, what do we do with these stem cells?  As I said, there are two kinds of things we want to think about using them for.  One is to make tissues and organs, as I’ve already described with the human heart.  But let’s talk about how we can use them to replace tissues in the diseased state and/or use them as tools to discover new drugs.  So now I want to talk about why scientists are so excited about embryonic stem cells and stem cells in general and how we plan to use them.   

This requires that I remind you where we are in biomedicine in this era.  We’ve largely conquered the problem for many, but not all infectious diseases.  What our society suffers from now, to a large extent is what I would call degenerative diseases.  These are diseases where parts of our brain and our nervous system degenerate.  For example, in Alzheimer’s, four brain basil neurons degenerate.  In Parkinson’s it’s a cell that makes the chemical signal, Dopamine, right in the mid brain, which is lost.  In a motor neuron disease, sometimes called Lou Gehrig’s Disease, can be abbreviated ALS for Amyotrophic Lateral Sclerosis, the nerves that innervate our muscles and make us move, allow us to breath, allow us to do all of our movement, degenerate.  Cardiovascular disease is a disease, of course of the heart and the blood vessels.  And the disease I am particular interested in and focused on is diabetes.    

What all of these degenerative diseases have in common is that they have a genetic makeup that inclines the patient to get the disease, but doesn’t guarantee that they will get it.  There’s another factor, an environmental factor, which you could say, pushes a person over the edge and causes them to get the disease.  A good example would be of an environmental factor would be the sun for skin cancer, or smoking for lung cancer.  A person may be inclined to get one of those diseases, one of those cancers, but it’s the environmental factor that pushes it over the edge.   

We know this is true furthermore because there are many cases of identical twins, two people with the same genes, where one has one of these degenerative diseases and the other one doesn’t showing therefore that there is an as yet unknown environmental factor that therefore causes one to get juvenile diabetes.   

So I’d now like to address the potential of stem cells to replace tissues and to use them as tools to discover drugs for degenerative diseases. 

Stem Cells and Degenerative Disease

I haven’t talked much about degenerative diseases, so let me explain what I mean by them.   

Degenerative diseases are diseases where a particular cell type in the body becomes dysfunctional or destroyed.  In the case of neuro degeneration, that would be in the fore brain, basil neurons in the fore brain are lost in the disease known as Alzheimer’s.  In Parkinson’s disease, it’s a different neuron.  A neuron in the mid brain that makes a chemical signal called Dopamine.  Another kind of neuro degenerative disease is sometimes called Lou Gehrig’s disease or Amyotrophic Lateral Sclerosis.  It’s a real mouthful and we usually abbreviate it as ALS.  That’s a disease where the nerves that innervate your muscles are degenerated and you can no longer move, you can’t breathe and you unfortunately die from that.  There’s no treatment for it.   

Another disease of the degeneration would be cardiovascular disease.  A disease of the heart tissue or the blood vessels which degenerate over time leading to heart attacks and possibly death.  The disease I work on, diabetes is one where our body’s metabolism can’t function anymore often because a cell in the pancreas that makes insulin is lost and therefore there is no insulin and we can’t make use of the food that we eat and it leads to the disease of diabetes.   

I’d like to talk then about how we can treat these diseases with stem cells by focusing on the fact that in each of these cases, a single kind of cell is lost.  In the case of diabetes, the cell which is lost is a cell in the pancreas called the beta cell, which makes insulin.  There are two types of diabetes.  There’s adult onset, usually related to obesity where people don’t initially use their insulin producing cells, but about 10 percent of that population eventually loses them and becomes insulin dependent.  The type of diabetes that I work on is called juvenile or Type I diabetes, which is an autoimmune disease where the body’s own immune system wrongly identifies its own cells, its own pancreatic beta cells and kills them off leaving the patient without the ability to make insulin and therefore requiring regular insulin injections.   

It might be worth pointing out that all of these degenerative diseases like diabetes have an enormous social and health consequence on the individual, but also a really enormous economic consequence on our society.  It’s estimated, for example by the U.S. government, that the cost of treating diabetes in America runs on the order of about $178 billion, not million, billion dollars per year.  So these are very important social and health problems that we would like to address.   

So back to diabetes.  ese islets, which contain the insulin producing cells within them.   

In a Type I diabetic, as I’ve said, the body attacks those blue cells and eliminates them.  In this picture here, you see that the blue cells are gone, there is no insulin producing cells and the patient is now entirely dependent on daily blood glucose checks and the insulin injections.   

The way this can be treated now, which doesnLet’s talk about how we might use stem cells to treat diabetes.  Well, if the cells in the pancreas are lost, they would look something like this.  The blue cells here are cells that have been stained with an antibody for insulin.  So they are the cells in your body that make the hormone, insulin.  Every human has about 800,000 to a million of these little spheres, th’t work for a large number of people, but has been demonstrated to work, is that human islets can be isolated from cadavers, it usually takes two cadavers to prepare enough islets, those shown here in red are the insulin producing cells and they can be transplanted into a diabetic and that can make that person independent of insulin injections for many years.   

What we’d like to do then is to make islet cells.  That is the pancreatic insulin-producing beta cells from human embryonic stem cells.  The way we go about doing that is to first understand how beta cells are normally made and then we try to recapitulate or reproduce that using human embryonic stem cells.  So our starting material then is an ES cell, or the induced pluripotent stem cell, in both cases coming from a human.  We then first have to instruct it, to tell it to become part of the gut tube, the endoderm.  It needs other instructions to tell it to become part of the pancreas, within the pancreas it has to become endocrine, a hormone producing cell, and then finally we have to reach our target of the human beta cell.   

We’re not there yet, but I’m confident that we’re going to be able to make bucket loads of these beta cells in the next few years.  And as I’ve indicated before, this is just one application for human embryonic stem cells.  If we go back to look at the list of these degenerative diseases, many investigators are working on how to make midbrain neurons to treat Parkinson’s patients, motor neurons for ALS, cardiac muscle cells, I’ve already shown and I just mentioned pancreatic beta cells for Type I diabetes.   

So one big grand goal of the use of human embryonic stem cells is to make cells which are deficient in disease and use those for transplantation.  In the next few years, I predict we will be able to see major advances in that for treatment of diabetes and some neurodegenerative diseases.   

There is, however, another completely independent or parallel path where stem cells are used, not as products to put into people, but are used a tools for drug discovery.  So drugs, of course, are small molecules of chemicals that you take to change your body’s Phenotype, your body’s activity.  I’d like to describe an example where quite a lot of progress has been made.  I’d like to describe an example where quite a lot of progress has been made in studying the neurodegenerative diseases, one in which motor neurons are lost.   

The idea for this experiment is to take embryonic stem cells from a patient who suffers from Lou Gehrig’s disease, ALS, or a similar disease called spinal muscular atrophy.  In both cases where motor neurons are lost.  Turn those cells into motor neurons and then have a control or similar cell from a patient that doesn’t have the disease, from a volunteer.  What we call control embryonic stem cells.  The idea here then is to use those cells in petri dishes and then in plates, kind of like bingo cards where all of the cells are spread out and screen for chemicals or potential drugs that slow the degeneration, that stop the progression of this disease.   

In the example I’ll give in this experiment is to use motor neurons that have been derived from stem cells.  In one case from cells that have genes that cause a person to get the disease and in the other case not.  The important point to see here is that if we use the control cells, the rate at which they die in a petri dish goes from the blue bars on the left to the right where you see the cells slowly dying.  In the case where we use cells from a patient, the cells die much more quickly.  

The red bars show that these motor neurons die very quickly in a petri dish.  This allows us to set up an assay to look for a drug that will slow the progress of the disease.  And tantalizingly, we’ve already found some examples where this could work.  The green shows the amount of a protein that is important for motor neuron life for survival.  And the minus sign, the drug has not been added.  In the plus sign it has.  And you can see much more green and red protein when we add the drug.   

So what does this mean?  This means, looking ahead, that it may be possible in the next few years to find drugs, not to cure motor neuron disease or that reverse the loss that’s already happened, but instead to simply slow the progress of the disease.  Well you might say, that’s not such a high bar, you just want to slow the progress, but let me remind you that if you’re unfortunate enough to be diagnosed with a disease like ALS, generally speaking, people don’t survive more than three to six years.  So if we found a drug which slowed down that degenerative process, we may be able to add significant amounts of time to their life.  We could double that from three to six to maybe six to 12 more years, which would really be significant.   

It is in the end, however, not fun to be thinking about all of these degenerative diseases that we or our loved ones are going to suffer from.  And so I’d like to end by talking about another aspect of stem cell biology which has nothing to do with disease, but instead, has to do with the natural progress of aging and how we might use stem cells to mediate against that.  

Stem Cells and Aging

So harnessing stem cell biology for something I would call healthy aging.  Aging is so obvious I hardly need to explain with it is.  We all know that we age and we sense it and feel it in our own bodies.  Here’s a nice picture of looking at a young woman who ages and you see that over time, here body changes.  It’s the same person, cells have been replaced, but here body’s capacity for replenishment has declined over a period of some decades.   

So what do we really know about aging?  Well the characteristics are sort of obvious.  One is, as a young person, you’re organs are quite robust, your wounds heal very rapidly, and there’s a high tissue turnover rate.  As one ages, the ability to do all of those things declines.  In an older person, the organs are more frail, wounds heal very slowly and there’s a low tissue turnover rate.  So we believe by looking at the biology of stem cells, we can change the rate of that process.  Not reverse it, nor can we make it stop, but we can slow it down so that one would enjoy a life with, let’s call it, a younger, healthier body.   

I’m going to show you one experiment which has given us confidence that this can happen.  This involves putting to mice together in what we call parabiotic mice.  And it’s a kind of experiment I call, The Fountain of Youth Experiment.  What we do in this experiment is remove the outer skin of two mice and sew them together; kind of like Siamese Twins.  So we now have a young mouse and an old mouse sewn together.  And the consequence of that is that they share their blood stream.  They’re really quite happy.  They continue to live a long life and run around in the cage and eat and play as they normally would.   

The experiment I’m going to show you has to do with injuring the muscle in the mice and then asking whether there’s anything special about being young which allows your body to repair better.  In fact, I’ll remind you that when you were a little boy or little girl, it was commonplace for you to say, fall of your bike or have an accident and then not even remember it a few days later.  Your body was, as I’ve already said, very good at tissue repair and healing.  As you age, that ability to repair muscle and heal, fix your bruises as it were, slows down.  So when I fall of my bike now, I not only remember it the next day, I remember it for several weeks.  It takes my body a much longer time to repair itself.  So this experiment is designed to get at what is it about a young person that allows them to repair their muscle at a fast rate?   

The experiment here shows a panel in blue in the middle, which I’d like to draw your attention to.  And what we do is we take these two mice, which are parabiotic, and in the control experiment, the mice have their thigh muscle injured.  It’s kind of a bruise as you would get, some might call it a Charlie Horse.  What you can see that when we take parabiotic mice and injure the thigh muscle in one of them, and the “Y” stands for young, the muscle repair rate occurs normally, the same as if the mice were not paired together.     
The second thing is control experiment shows is that pairing a young mouse with an old mouse does not diminish the young mouse’s ability to repair its muscle.  So the amount of new red cells is the same.   

And other control is to compare two old mice, put them together and injure the old mouse’s muscle.  And here you see far fewer red cells.  The repair rate is very slow.  But the key result, the one you can guess is coming shown here at the end is to pair a young mouse with an old mouse and now injure the muscle in the old mouse, and sure enough, look at all those red cells.  The old mouse has not been rejuvenated as it were.  It’s repairing its muscle at the young rate.   

So we dearly would like to know, what is it in young blood that stimulates muscle stem cells in an old mouse to make it repair better?  This raises the question of what other aspects of aging might be affected by young factors.  Might I have to do with our loss of memory, with our heart function?  So we’re very keen to pursue these kinds of experiments, finding out what is it in a young animal that stimulates old stem cells, as it were, to make them young again.   

So you can imagine a time when you might go to your doctor and she would say, well, your liver is looking a little tired or you’re muscles are not repairing well or your bone isn’t as strong as it could be, but don’t worry, we have some stem cells that we’ve taken from you when you were a bit younger.  We’re going to put those in, top you up and you’re going to be good as new.   

The main points I’ve tried to make today can really be summarized as follows.  All of the cells in your body have an amazing potential.  This is what got me interested in biology.  It was discovered by cloning and it is to me still, such a mysterious and wondrous thing.  I’d like to know how we can harness that potential in our cells to repair our bodies and understand disease.   
I’ve shown some examples where stem cells can be used to replace body parts and find the root cause of disease.  Finally, stem cells and the biology of regeneration… and the biology of regeneration hold out the prospect for really healthy aging.  This will then lead in the longer term to designing our bodies and you might even say, designing babies.  How do we use this information and should we use this information to affect our phenotype and those of subsequent generations.  Thank you.   

So to summarize what I’ve talked about today, it’s what I see as a new era of medicine based in regenerative biology.  It starts from the fact, the amazing fact, that all of the cells in the body have this potential to make other kinds of cells.  This has led to the discovery of human embryonic stem cells and other stem cells, which we’d now like to use to replace tissue and body parts and use to understand the root causes of disease.  

I think you’ll see soon that that will also lead to the possibility of a healthier life, what I call healthy aging, where we’re not trying to fix you because you’ve had some disease or injury, but rather just replenish your body to maintain its young and vibrant state.  This will inevitably lead to the possibility of changing our bodies in a way that was previously unimaginable.   

This will inevitably lead to changing our bodies in a way that was previously unimaginable.  It will have to do not only with designing our bodies, but thinking about how we might design or determine what is the phenotype of our babies.  Thank you.

 

Professor Douglas Melton begins with a look at the basis for regenerative medicine, the human body’s ability to divide, grow, and specialize cells. With a solid foothold in developmental biology, we see how this knowledge led to the breakthrough cloning experiments we’re all familiar with: Hello, Dolly! Next, we’re introduced to the science of stem cells and their greatest hope: new "man-made" stem cells that could soon be used to reverse incurable degenerative diseases like diabetes, heart disease, and Alzheimer’s. Lastly, Professor Melton tells how these same stem cells may be the keys that unlock an end to aging as we know it.

Scientists see 'rarest event ever recorded' in search for dark matter

The team caught a glimpse of a process that takes 18,000,000,000,000,000,000,000 years.

Image source: Pixabay
Surprising Science
  • In Italy, a team of scientists is using a highly sophisticated detector to hunt for dark matter.
  • The team observed an ultra-rare particle interaction that reveals the half-life of a xenon-124 atom to be 18 sextillion years.
  • The half-life of a process is how long it takes for half of the radioactive nuclei present in a sample to decay.
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Yale scientists restore brain function to 32 clinically dead pigs

Researchers hope the technology will further our understanding of the brain, but lawmakers may not be ready for the ethical challenges.

Still from John Stephenson's 1999 rendition of Animal Farm.
Surprising Science
  • Researchers at the Yale School of Medicine successfully restored some functions to pig brains that had been dead for hours.
  • They hope the technology will advance our understanding of the brain, potentially developing new treatments for debilitating diseases and disorders.
  • The research raises many ethical questions and puts to the test our current understanding of death.

The image of an undead brain coming back to live again is the stuff of science fiction. Not just any science fiction, specifically B-grade sci fi. What instantly springs to mind is the black-and-white horrors of films like Fiend Without a Face. Bad acting. Plastic monstrosities. Visible strings. And a spinal cord that, for some reason, is also a tentacle?

But like any good science fiction, it's only a matter of time before some manner of it seeps into our reality. This week's Nature published the findings of researchers who managed to restore function to pigs' brains that were clinically dead. At least, what we once thought of as dead.

What's dead may never die, it seems

The researchers did not hail from House Greyjoy — "What is dead may never die" — but came largely from the Yale School of Medicine. They connected 32 pig brains to a system called BrainEx. BrainEx is an artificial perfusion system — that is, a system that takes over the functions normally regulated by the organ. The pigs had been killed four hours earlier at a U.S. Department of Agriculture slaughterhouse; their brains completely removed from the skulls.

BrainEx pumped an experiment solution into the brain that essentially mimic blood flow. It brought oxygen and nutrients to the tissues, giving brain cells the resources to begin many normal functions. The cells began consuming and metabolizing sugars. The brains' immune systems kicked in. Neuron samples could carry an electrical signal. Some brain cells even responded to drugs.

The researchers have managed to keep some brains alive for up to 36 hours, and currently do not know if BrainEx can have sustained the brains longer. "It is conceivable we are just preventing the inevitable, and the brain won't be able to recover," said Nenad Sestan, Yale neuroscientist and the lead researcher.

As a control, other brains received either a fake solution or no solution at all. None revived brain activity and deteriorated as normal.

The researchers hope the technology can enhance our ability to study the brain and its cellular functions. One of the main avenues of such studies would be brain disorders and diseases. This could point the way to developing new of treatments for the likes of brain injuries, Alzheimer's, Huntington's, and neurodegenerative conditions.

"This is an extraordinary and very promising breakthrough for neuroscience. It immediately offers a much better model for studying the human brain, which is extraordinarily important, given the vast amount of human suffering from diseases of the mind [and] brain," Nita Farahany, the bioethicists at the Duke University School of Law who wrote the study's commentary, told National Geographic.

An ethical gray matter

Before anyone gets an Island of Dr. Moreau vibe, it's worth noting that the brains did not approach neural activity anywhere near consciousness.

The BrainEx solution contained chemicals that prevented neurons from firing. To be extra cautious, the researchers also monitored the brains for any such activity and were prepared to administer an anesthetic should they have seen signs of consciousness.

Even so, the research signals a massive debate to come regarding medical ethics and our definition of death.

Most countries define death, clinically speaking, as the irreversible loss of brain or circulatory function. This definition was already at odds with some folk- and value-centric understandings, but where do we go if it becomes possible to reverse clinical death with artificial perfusion?

"This is wild," Jonathan Moreno, a bioethicist at the University of Pennsylvania, told the New York Times. "If ever there was an issue that merited big public deliberation on the ethics of science and medicine, this is one."

One possible consequence involves organ donations. Some European countries require emergency responders to use a process that preserves organs when they cannot resuscitate a person. They continue to pump blood throughout the body, but use a "thoracic aortic occlusion balloon" to prevent that blood from reaching the brain.

The system is already controversial because it raises concerns about what caused the patient's death. But what happens when brain death becomes readily reversible? Stuart Younger, a bioethicist at Case Western Reserve University, told Nature that if BrainEx were to become widely available, it could shrink the pool of eligible donors.

"There's a potential conflict here between the interests of potential donors — who might not even be donors — and people who are waiting for organs," he said.

It will be a while before such experiments go anywhere near human subjects. A more immediate ethical question relates to how such experiments harm animal subjects.

Ethical review boards evaluate research protocols and can reject any that causes undue pain, suffering, or distress. Since dead animals feel no pain, suffer no trauma, they are typically approved as subjects. But how do such boards make a judgement regarding the suffering of a "cellularly active" brain? The distress of a partially alive brain?

The dilemma is unprecedented.

Setting new boundaries

Another science fiction story that comes to mind when discussing this story is, of course, Frankenstein. As Farahany told National Geographic: "It is definitely has [sic] a good science-fiction element to it, and it is restoring cellular function where we previously thought impossible. But to have Frankenstein, you need some degree of consciousness, some 'there' there. [The researchers] did not recover any form of consciousness in this study, and it is still unclear if we ever could. But we are one step closer to that possibility."

She's right. The researchers undertook their research for the betterment of humanity, and we may one day reap some unimaginable medical benefits from it. The ethical questions, however, remain as unsettling as the stories they remind us of.

Why compassion fades

A scientific look into a ubiquitous phenomenon.

Photo credit: Adrian Swancar on Unsplash
Sex & Relationships

One victim can break our hearts. Remember the image of the young Syrian boy discovered dead on a beach in Turkey in 2015? Donations to relief agencies soared after that image went viral. However, we feel less compassion as the number of victims grows. Are we incapable of feeling compassion for large groups of people who suffer a tragedy, such as an earthquake or the recent Sri Lanka Easter bombings? Of course not, but the truth is we aren't as compassionate as we'd like to believe, because of a paradox of large numbers. Why is this?

Compassion is a product of our sociality as primates. In his book, The Expanding Circle: Ethics, Evolution, and Moral Progress, Peter Singer states, "Human beings are social animals. We were social before we were human." Mr. Singer goes on to say, "We can be sure that we restrained our behavior toward our fellows before we were rational human beings. Social life requires some degree of restraint. A social grouping cannot stay together if its members make frequent and unrestrained attacks on one another."

Attacks on ingroups can come from forces of nature as well. In this light, compassion is a form of expressed empathy to demonstrate camaraderie.

Yet even after hundreds of centuries of evolution, when tragedy strikes beyond our community, our compassion wanes as the number of displaced, injured, and dead mounts.

The drop-off in commiseration has been termed the collapse of compassion. The term has also been defined in The Oxford Handbook of Compassion Science: ". . . people tend to feel and act less compassionately for multiple suffering victims than for a single suffering victim."

That the drop-off happens has been widely documented, but at what point this phenomenon happens remains unclear. One paper, written by Paul Slovic and Daniel Västfjäll, sets out a simple formula, ". . . where the emotion or affective feeling is greatest at N =1 but begins to fade at N = 2 and collapses at some higher value of N that becomes simply 'a statistic.'"

The ambiguity of "some higher value" is curious. That value may relate to Dunbar's Number, a theory developed by British anthropologist, Robin Dunbar. His research centers on communal groups of primates that evolved to support and care for larger and larger groups as their brains (our brains) expanded in capacity. Dunbar's is the number of people with whom we can maintain a stable relationship — approximately 150.

Some back story

Professor Robin Dunbar of the University of Oxford has published considerable research on anthropology and evolutionary psychology. His work is informed by anthropology, sociology and psychology. Dunbar's Number is a cognitive boundary, one we are likely incapable of breaching. The number is based around two notions; that brain size in primates correlates with the size of the social groups they live among and that these groups in human primates are relative to communal numbers set deep in our evolutionary past. In simpler terms, 150 is about the maximum number of people with whom we can identify with, interact with, care about, and work to protect. Dunbar's Number falls along a logorithmic continuum, beginning with the smallest, most emotionally connected group of five, then expanding outward in multiples of three: 5, 15, 50, 150. The numbers in these concentric circles are affected by multiple variables, including the closeness and size of immediate and extended families, along with the greater cognitive capacity of some individuals to maintain stable relationships with larger than normal group sizes. In other words, folks with more cerebral candlepower can engage with larger groups. Those with lesser cognitive powers, smaller groups.

The number that triggers "compassion collapse" might be different for individuals, but I think it may begin to unravel along the continuum of Dunbar's relatable 150. We can commiserate with 5 to 15 to 150 people because upon those numbers, we can overlay names and faces of people we know: our families, friends and coworkers, the members of our clan. In addition, from an evolutionary perspective, that number is important. We needed to care if bands of our clan were being harmed by raids, disaster, or disease, because our survival depended on the group staying intact. Our brains developed the capacity to care for the entirety of the group but not beyond it. Beyond our ingroup was an outgroup that may have competed with us for food and safety and it served us no practical purpose to feel sad that something awful had happened to them, only to learn the lessons so as to apply them for our own survival, e.g., don't swim with hippos.

Lapses

Imagine losing 10 family members in a house fire. Now instead, lose 10 neighbors, 10 from a nearby town, 10 from Belgium, 10 from Vietnam 10 years ago. One could almost feel the emotion ebbing as the sentence drew to a close.

There are two other important factors which contribute to the softening of our compassion: proximity and time. While enjoying lunch in Santa Fe, we can discuss the death toll in the French revolution with no emotional response but might be nauseated to discuss three children lost in a recent car crash around the corner. Conflict journalists attempt to bridge these geotemporal lapses but have long struggled to ignite compassion in their home audience for far-flung tragedies, Being a witness to carnage is an immense stressor, but the impact diminishes across the airwaves as the kilometers pile up.

A Dunbar Correlation

Where is the inflection point at which people become statistics? Can we find that number? In what way might that inflection point be influenced by the Dunbar 150?

"Yes, the Dunbar number seems relevant here," said Gad Saad, PhD., the evolutionary behavioral scientist from the John Molson School of Business at Concordia University, Montreal, in an email correspondence. Saad also recommended Singer's work.

I also went to the wellspring. I asked Professor Dunbar by email if he thought 150 was a reasonable inflection point for moving from compassion into statistics. He graciously responded, lightly edited for space.

Professor Dunbar's response:

"The short answer is that I have no idea, but what you suggest is perfect sense. . . . One-hundred and fifty is the inflection point between the individuals we can empathize with because we have personal relationships with them and those with whom we don't have personalized relationships. There is, however, also another inflection point at 1,500 (the typical size of tribes in hunter-gatherer societies) which defines the limit set by the number of faces we can put names to. After 1,500, they are all completely anonymous."

I asked Dunbar if he knows of or suspects a neurophysiological aspect to the point where we simply lose the capacity to manage our compassion:

"These limits are underpinned by the size of key bits of the brain (mainly the frontal lobes, but not wholly). There are a number of studies showing this, both across primate species and within humans."

In his literature, Professor Dunbar presents two reasons why his number stands at 150, despite the ubiquity of social networking: the first is time — investing our time in a relationship is limited by the number of hours we have available to us in a given week. The second is our brain capacity measured in primates by our brain volume.

Friendship, kinship and limitations

"We devote around 40 percent of our available social time to our 5 most intimate friends and relations," Dunbar has written, "(the subset of individuals on whom we rely the most) and the remaining 60 percent in progressively decreasing amounts to the other 145."

These brain functions are costly, in terms of time, energy and emotion. Dunbar states, "There is extensive evidence, for example, to suggest that network size has significant effects on health and well-being, including morbidity and mortality, recovery from illness, cognitive function, and even willingness to adopt healthy lifestyles." This suggests that we devote so much energy to our own network that caring about a larger number may be too demanding.

"These differences in functionality may well reflect the role of mentalizing competencies. The optimal group size for a task may depend on the extent to which the group members have to be able to empathize with the beliefs and intentions of other members so as to coordinate closely…" This neocortical-to-community model carries over to compassion for others, whether in or out of our social network. Time constrains all human activity, including time to feel.

As Dunbar writes in The Anatomy of Friendship, "Friendship is the single most important factor influencing our health, well-being, and happiness. Creating and maintaining friendships is, however, extremely costly, in terms of both the time that has to be invested and the cognitive mechanisms that underpin them. Nonetheless, personal social networks exhibit many constancies, notably in their size and their hierarchical structuring." Our mental capacity may be the primary reason we feel less empathy and compassion for larger groups; we simply don't have the cerebral apparatus to manage their plights. "Part of friendship is the act of mentalizing, or mentally envisioning the landscape of another's mind. Cognitively, this process is extraordinarily taxing, and as such, intimate conversations seem to be capped at about four people before they break down and form smaller conversational groups. If the conversation involves speculating about an absent person's mental state (e.g., gossiping), then the cap is three — which is also a number that Shakespeare's plays respect."

We cannot mentalize what is going on in the minds of people in our groups much beyond our inner circle, so it stands to reason we cannot do it for large groups separated from us by geotemporal lapses.

Emotional regulation

In a paper, C. Daryl Cameron and Keith B. Payne state, "Some researchers have suggested that [compassion collapse] happens because emotions are not triggered by aggregates. We provide evidence for an alternative account. People expect the needs of large groups to be potentially overwhelming, and, as a result, they engage in emotion regulation to prevent themselves from experiencing overwhelming levels of emotion. Because groups are more likely than individuals to elicit emotion regulation, people feel less for groups than for individuals."

This argument seems to imply that we have more control over diminishing compassion than not. To say, "people expect the needs of large groups to be potentially overwhelming" suggests we consciously consider what that caring could entail and back away from it, or that we become aware that we are reaching and an endpoint of compassion and begin to purposely shift the framing of the incident from one that is personal to one that is statistical. The authors offer an alternative hypothesis to the notion that emotions are not triggered by aggregates, by attempting to show that we regulate our emotional response as the number of victims becomes perceived to be overwhelming. However, in the real world, for example, large death tolls are not brought to us one victim at a time. We are told, about a devastating event, then react viscerally.

If we don't begin to express our emotions consciously, then the process must be subconscious, and that number could have evolved to where it is now innate.

Gray matter matters

One of Dunbar's most salient points is that brain capacity influences social networks. In his paper, The Social Brain, he writes: "Path analysis suggests that there is a specific causal relationship in which the volume of a key prefrontal cortex subregion (or subregions) determines an individual's mentalizing skills, and these skills in turn determine the size of his or her social network."

It's not only the size of the brain but in fact, mentalizing recruits different regions for ingroup empathy. The Stanford Center for Compassion and Altruism Research and Education published a study of the brain regions activated when showing empathy for strangers in which the authors stated, "Interestingly, in brain imaging studies of mentalizing, participants recruit more dorsal portions of the medial prefrontal cortex (dMPFC; BA 8/9) when mentalizing about strangers, whereas they recruit more ventral regions of the medial prefrontal cortex (BA 10), similar to the MPFC activation reported in the current study, when mentalizing about close others with whom participants experience self-other overlap."⁷

It's possible the region of the brain that activates to help an ingroup member evolved for good reason, survival of the group. Other regions may have begun to expand as those smaller tribal groups expanded into larger societies.

Rabbit holes

There is an eclectic list of reasons why compassion may collapse, irrespective of sheer numbers:

(1) Manner: How the news is presented affects viewer framing. In her book, European Foreign Conflict Reporting: A Comparative Analysis of Public News, Emma Heywood explores how tragedies and war are offered to the viewers, which can elicit greater or lesser compassionate responses. "Techniques, which could raise compassion amongst the viewers, and which prevail on New at Ten, are disregarded, allowing the victims to remain unfamiliar and dissociated from the viewer. This approach does not encourage viewers to engage with the sufferers, rather releases them from any responsibility to participate emotionally. Instead compassion values are sidelined and potential opportunities to dwell on victim coverage are replaced by images of fighting and violence."

(2) Ethnicity. How relatable are the victims? Although it can be argued that people in western countries would feel a lesser degree of compassion for victims of a bombing in Karachi, that doesn't mean people in countries near Pakistan wouldn't feel compassion for the Karachi victims at a level comparable to what westerners might feel about a bombing in Toronto. Distance has a role to play in this dynamic as much as in the sound evolutionary data that demonstrate a need for us to both recognize and empathize with people who look like our communal entity. It's not racism; it's tribalism. We are simply not evolved from massive heterogeneous cultures. As evolving humans, we're still working it all out. It's a survival mechanism that developed over millennia that we now struggle with as we fine tune our trust for others.

In the end

Think of compassion collapse on a grid, with compassion represented in the Y axis and the number of victims running along the X. As the number of victims increases beyond one, our level of compassion is expected to rise. Setting aside other variables that may raise compassion (proximity, familiarity etc.), the level continues to rise until, for some reason, it begins to fall precipitously.

Is it because we've become aware of being overwhelmed or because we have reached max-capacity neuron load? Dunbar's Number seems a reasonable place to look for a tipping point.

Professor Dunbar has referred to the limits of friendship as a "budgeting problem." We simply don't have the time to manage a bigger group of friends. Our compassion for the plight of strangers may drop of at a number equivalent to the number of people with who we can be friends, a number to which we unconsciously relate. Whether or not we solve this intellectual question, it remains a curious fact that the larger a tragedy is, the more likely human faces are to become faceless numbers.