Unlocking the Code of Life

So we have a number of topics that we are
going to talk about today but first one is aging, both of you have worked and spoken
a great deal on aging and we all grow up feeling intuitively that aging is this inevitable
process. And at the same time, we do this crazy thing that you can have a 30yearold
woman and a 30yearold man and somehow they come together and create a zeroyearold person
which is kind of crazy when you think about it.
So the first question for both of you is: Is aging inevitable? And is it reversible,
maybe starting with you, Liz? Well, I think you answered the question right
away. When you think about our germ cells from generation to generation produce amazing
new babies, then clearly, this immortal lineage can happen. And I think when we figure that
out, and there’s a lot of research that points towards why these cells do so well, how they
preserve their genomes so well and how they clean up their proteins so well. Then we have
got mechanisms there. Now, there’s a lot of things that we have to take care of if we
are going to also play that out in the very complex system of our human bodies with its,
you know, trillions of cells, not to mention the microbiome to coexist and the change the
expression as we exist. But it’s not inevitable, we are sort of an accident of evolution that
we happen to have the life spans that we do and we are a giant experiment on the plant
et cetera because until very recent history, we never, really, mostly as a species lived
to extreme old age. So we are just  you know, we are an experimenter
of the 7.5 billion souls going on as we speak. And George, you famously said we are on the
beginning of age reversal, something I have written about as well. What do you mean by
that? And how close are we? It’s easier to do experiments where the time
horizon is five weeks and 50 years to get FDA approval, it’s easier. Aging reversal
is not science fiction, it  we have many examples not just the example of reversal
when we procreate but we can do that  we can reprogram my 63yearold fibroblasts into
stem cells with four transcription factors, and they have been made quite famous.
You cannot only do that in cell culture. You can do it in animals as well. Plus  and there
are many other examples of aging reversal that are well documented in animals, where
you can get factors from the blood, that we’re characterizing or more.
They are even small molecules that have been discovered from  for many different ways
including observing the effects of small molecule drugs on diabetics and seeing the off label
advances that occur with that like metformin. We will talk about some of the mechanisms
of aging that you have been referring to. So Liz, your Nobel Prize was in understanding
telomeres. Give the audience a little bit of background about what are telomeres and
why are they important for aging? Are genes are housed in chromosomes, but they
have a lot of genetic material in them, and at the end of the chromosomes we think of 
if you think of a shoe lace it’s like the little protective tip at the end that stops
the shoe lace end fraying away. We know a lot about the molecular nature of that, and
the bottom line is that when that telomeric end wears down, that sends a tremendous signal
to a cell that says, oops, genetic material in danger and the cell sends off alarm signals
and won’t work properly as a cell, bottom line.
That turns out in the long trajectories of decades of human life to start to happen in
our lives that wearing down really does happen. And there are sequences which have been proven
genetically, you know, lots of different ways, that this is a contributor to things like
very common diseases of mortality  that cause mortality, cardiovascular.
If you have a certain set of variance that change your telomere maintenance and this
was just found by objectively looking across the genome, you start out of the gate with
about a 20% higher chance of getting cardiovascular disease of various kinds.
So genes that maintain your telomeres matter and how they maintained matters, and it turned
out that that was very interesting because there was a lot of life factors that changed
how well your telomeres are maintained. And I think very much connected with the talk
we just heard, the marvelous talk about how important it is our interactions, our connectedness,
we found over and over again, and many others too, so this is not just I and my collaborators,
many have found that the more connected you are, the more social support, the more rich
your family relationships, the more  the more you trust your neighborhood, those things
all quantifiably related to better telomere maintenance.
So your mind is having real physiological readouts that have healthrelated effects.
So it’s a very interesting cyclical nature to all of this.
And it’s very interesting because in the early days of when your research was coming out,
it was identified that telomerase, and my mother called me where do I get my telomerase.
And this then it was determined it was dangerous. How do you live a life where you feel safe.
How do you live a life where you are reducing the amount of stress on your body.
So George, moving to other mechanisms, you mentioned the Yamanaka factor. He won the
2012 Nobel Prize for identifying these four factors that create what are called induced
pluripotent stem cells so an adult cell can become a stem cell. How do you use the Yamanaka
factors to reverse aged mice. Maybe talk a little bit about that and about parabiosis,
looking at how an old mouse gets younger and a young mouse gets older.
Yes, these have both been well established in animals, worms, flies and mice, mainly,
where you can either get longevity, where from birth they have the right genes or they
are a smaller subset of experiments where you actually reverse it during their lifetime,
including the Yamanaka factors and the  and the blood components.
If you look, there’s about  there’s a database of hundreds of these genes that have been
well curated, and what we’re doing is turning them into gene therapies. This is a very good
way of doing both rapid prototyping but also possibly a mature therapy, they are now 2400
gene therapies in clinical trials and it’s very easy to go from a hypothesis from the
literature to a gene therapy. We can do 60 at once, with just a couple of postdocs. And
we take preaged mice who are 2 years old and then the gene therapies that work in those,
we move into preaged dogs, 12 years old and we are looking for things that have an effect
there. We are looking for something that has a bodywide
physiological impact. And Liz, you were saying earlier that you
were just with Tony WyssCoray talking about parabiosis, maybe give your thoughts on parabiosis.
That was the original way of doing it, what was it in the blood that exchanged between
the animals and now, of course, people are narrowing in and there are, indeed, protein
factors that are being seen, perhaps it’s going to be a combination of them, that have
been seen to be part of this. So I think you won’t need to have your  you
know, your blood donor as we rather grotesquely talked about.
The blood boy from Silicon Valley. Like some of these things that start off with
a complex mixture of what’s in the blood, it looks like they are soluble protein factors.
We may find a cocktail. One of the fascinating things about aging, there are proteins, the
very same molecules can sit in your brain or your heart, it seems like, you know, for
life and not get fixed when they get damaged and so  and yet there are other cells that
are really good at turning over as we say and replacing damaged proteins.
So, you know, persuading cells to turn on these pathways so they could fix  you know,
replace their old worn down proteins. I call them zombie proteins. They are the undead.
They have sit there and they are damaged and you want them to go away. There will be different
aspects, as George says the reprogramming is certainly one way because that sets things
back into a more young state, including by the way, improving their telomere maintenance.
We have seen that. You have to take care of that before all the other parts will be taken
care of. Yes, and it’s very interesting because with
this, you are right, they are identifying, what are the factors that have this rejuvenating
impact and first, they were connecting these different mice, and then they were injecting
human cord blood into the old mice and those old mice also started to get younger in many
ways. And so cross species conserved mechanisms
which says the research on the mice models will be very helpful up to a point. And so,
I think that, you know but there might be multiple aspects of aging that one has to
take care of. And I think we have to think how long do we
want to be, you know, living these kinds of  this arc of our lives? I think that’s a huge
question that many people really kind of grapple with and comes to, you know, well, what is
a fulfilling, worth while life? And which years to you extend?
Somebody said, please, not the teenaged years. (Laughter).
I will take anything I can get. George, you have been doing a lot, studying centenarians
and longlived humans what would you say are the lessons studying them and how does that
lead to a path forward? Well, certainly, there are environmental components.
Mice live about two years and bowhead whales live 200 years. And there are human beings
that have exceeded 110, 120 years. And they are very youthful at that age.
And the hope is that if we can figure out what the components they have, which we can 
like, with the  just as with the parabiotic blood components, we can try them in various
combinations and various ratios to improve on what we have observed in nature.
It may be different. There may be one pathway to successful, but I’m struck by another species
or pair of species that there are called mole rats and they live, you know, many, decades
and they are very social and people have studied them. He they don’t die of cancer but they
live for very long ages. People were very excited and they said, what
is their secret? That’s an example in one species.
But another species they avoid cancer in a different way and they live long. I think
maybe the success we see in people, is not converging on one thing. Just like 
I sincerely hope so. Because that gives us a chance to put them all together.
Right. But there may be certain ones in certain settings that are more, you know, powerful
than others. Yeah.
So there’s a lot to learn about these really complex systems, which was why we need the
technologies to get us past, you know, this immense complexity that is life.
And just a short special message for our hosts, the Google calico has one of the largest example
of naked mole rats. Yes, they are the favorite species. You have
to look at other mole rats. Their secrets are not the same ones as the other species.
Writing and thinking and speaking a lot about, which is what you call precision interception.
We all know about precision medicine, personalized medicine, but what you are saying is let’s
move forward in the time frame. Don’t wait until somebody gets sick. Let’s figure out
what to look for and how to keep them healthy. Yes, why wait for the sword to fall on your
head, oh, I got cancer. Cancer doesn’t happen overnight. It develops over years as do you
know, some of the other major killers like cardiovascular, and diabetes.
More and more biology is being used about the earliest stages. So this can be made very
scientific and I like to use the word “interception” because it’s a continuum of, you know  there
can be very early stages which are not particularly, you know, maligned but can be averted. So,
you know, you want to intercept processes before they take hold and start to really
become pathological. And this is getting more and more realistic because you can capture,
I think more and more data about what’s going on early and put together what is happening
and then say, aha. Now for this person this interception makes
sense but for another person, another one might make better sense.
And we were talking about yesterday, I think what that leads to is our need to have, in
some ways, a much greater sensing environment, environment that is reading us. I mean, I
write science fiction and I can make things up, but I like the idea some day of my bathroom
being a sensor. That my mirror is watching me, is looking for changes. The toilet where
you are flushing all kinds of useful information down the toilet every day.
Your micro biome. It should be communicating with your smoothy
maker, that this person needs some extra iron. It makes sense.
And how about internally. I would like things cruising around, how are your telomeres. Nudge
upwards and get rid of a few cells that are getting cancer here.
Yeah. Yes. I think if we  and this is not totally science
fiction, but I think if we could really scrutinize what is going on, within the system  systemically
in the noninvasive ways using peco science and nano science is probably too big. You
may have to go even smaller. Science fiction and science fact are so overlapping.
You don’t need talk about where we are and where we are going. It blows people’s minds.
George, a lot of people are talking about CRISPR. What are the shortterm and mediumterm
applications of CRISPR? And you have said repeatedly that CRISPR is one school and there
will be more tools that will allow us to be more precise in the gene editing.
Right. To some extent, CRISPR  let’s start with the flaws. It is a serial killer, naturally.
It kills viruses in nature by scanning along the genome, looking for anything that they
recognize as some bad guy that they have seen before.
And they do that with about 20 base pairs of RNA is the main recognition element.
So that one of its limitations it just cuts. It doesn’t do the precise editing that we
would all like. There are other enzymes that do that and it’s just a matter of time before
they displace it. It also is inefficient. When you treat something
with CRISPR, you get a mosaic. Some are unaffected and some are affected in one way and some
affected in another way. You get a mosaic and we can look forward to that on the near
horizon. Most of these technologies get turned over
every four or five years. Nevertheless, there are powerful things that can be done.
There are 2400 gene therapies in clinical trials. Most are not gene editing but we will
see many more. That includes anything where you want to knock something out, where the
trouble is due to an excess of something, or a false version of something.
All the other gene therapies are about adding. This is about subtraction and finally, there
will be the precise editing in the future. We can use it for making transplantable organizations
from pigs. We can do it for, you know, public health efforts on using mosquitoes and  and
mice and other vectors of disease. There are agricultural applications as well.
Right. I think we 
I think just standing from here, recognizing just the tools that we have now, if we had
no new tools, we could revolutionize ourselves in the world. When we think that the tools
themselves are on an exponential curve. So we will be able to do things in the not distance
future that are unimaginable today and that, of course, raises a lot of figures. The fact
that we will have the tools to recode life, doesn’t mean that we will have the emotional,
intellectual, other types of maturity and business comas a species to smartly apply
those  apply those tools in a way that does more good than more harm.
This was a time in  in 2005 when the UN General Assembly had a resolution, and they were talking
about genome. They were talking about the germ line and they said it was with
the human DNA and the mitochondrial came into play.
There was a well researched document, it took about two plus years and just came out this
February, that came out with a slightly different conclusion which is that there are medical
reasons why you might intervene with germ line.
For example, there’s a large set of diseases, about 5% of children are born with very severe
genetic diseases that are very impactful psychosocial and economically, over $20 million are the
lifetime costs and those can be handled  right now the medical  the main medical way
they are being handled is through abortion. That’s not acceptable to everybody. This may
provide another way of engineering the sperm or eggs so that you can completely avoid risk
to embryos for this 5% of the population. You mentioned engineering sperm and eggs.
You didn’t mention engineering embryos. Right. Yes. And part of that is because that
doesn’t save embryos. That puts embryos at risk and so far, that’s producing mosaic embryos.
You can get, essentially 100% what you want, by screening the clones before you put them
in to replace the cells. And part of that suggests that we are going
to move towards IVF and embryo screening, just because so much is happening outside
of the traditional body. How do you see reproduction, Liz, evolving in light of these technological
revolutions that we have been discussing? Genes are very important, it’s a little bit
of the light under the lamp post. We understand them best. There’s a lot of other things that
do go on. Our epigenome that make genes come on and off, and that’s quite changeable throughout
life. Some day the beginning that it might be partly
heritable. So I think we  you know, we might  except for the case where George is talking
about, clearly a medical need can be met by correcting, you know, defective gene or a
gene that’s mutated in some way that causes harm.
Beyond that in terms of the predictable genomes. What does it predict in terms of the full
life of the person. We are only partly there. This may start to get more and more understood
as one gets lots of data and lots of individuals of their genomes, their epigenomes and the
cellular times because how those play out is in itself a whole world and you can have,
for example  just  genetically identical yeast cells and they normally divide about
25 times but actually, if you look at individual ones, some will just explode with a catastrophic
problem and some will explode after six and some after 40. What happened with the system’s
failure is a marvelous, probably approachable question with better tools.
But we need to understand the systems better, before we make too many in roads into things
that are not just curative. And that’s absolutely the level of complexity
is monumental. This is the ultimate big data problem. But as we move towards precision
medicine as you mentioned and everyone will have their sequence genome as the foundation
of their electric medical record and we will be able to compare the genome type and potentially
we will know more. And what can we learn from each other? I think
we will learn a lot about human diversities. We have millions of base pair changes among
us all and yet somehow the system works in this very compensated, fascinating way that
adapts. We are surely incredibly interesting creatures. Life on earth is really, really,
well worth that intellectual effort going into it, because it will not only help us,
but I think, you know, it’s sort of  it expands our horizons.
Absolutely. And this is all very exciting to people, and I think all of us speak to
people about this all the time. But it also scares people. And how do we find the balance
between making people  helping people understand this incredible promise and not scaring people
so much that they don’t feel that this science and this future is about them? George?
Well, a lot of it has to do with constant communication, and to some extent they should 
they should be scared occasionally. I mean, it’s  it’s good to have it so that you think
about it in advance and to bring things up that might be worthy of protecting ourselves
from them. In the end, usually it’s about safety and efficacy but there are some other
issues as well that are beyond the purview of the FDA that we can talk about in advance.
And he can think about when there are harms, how do we deal with harms as a society? You
know, one mechanism is, you know, there’s rules. There’s laws. There’s understood modes
of behavior. And, you know, we have to face that there are things that we probably do 
you know, we don’t condone murder, right? Even though that’s extremely possible, right,
to do it. And so there are things that we probably as
a society start thinking about but it’s all mixed in, as you said with sort of fear of
the unknown, which can be holding things back in ways that are not good.
And so I think it comes back dork we really have to start understanding and asking ourselves
what is it that is  you know, what is it that makes lives fulfilling and worth while,
and our interactions with others? It’s interesting. It sort of put us right back to some really
fundamental questions. And I think that’s the challenge with all
of this, that the technology is new and the wisdom and the values that we need to make
sense of it are in many ways old. But we can respect that if they are old.
We must. The technology is that the technology advancing exponentially and public understanding
is expanding linearly and the regulatory structures are only inching forward glacially: Thank
you so much.

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