1
99:59:59,999 --> 99:59:59,999
I'm going to tell you about the most
amazing machines in the world ...

2
99:59:59,999 --> 99:59:59,999
And what we can now do with them.

3
99:59:59,999 --> 99:59:59,999
Proteins,

4
99:59:59,999 --> 99:59:59,999
some of which you see inside a cell here,

5
99:59:59,999 --> 99:59:59,999
carry out essentially all the important
functions in our bodies.

6
99:59:59,999 --> 99:59:59,999
Proteins digest your food,

7
99:59:59,999 --> 99:59:59,999
contract your muscles,

8
99:59:59,999 --> 99:59:59,999
fire your neurons

9
99:59:59,999 --> 99:59:59,999
and power your immune system.

10
99:59:59,999 --> 99:59:59,999
Everything that happens in biology --

11
99:59:59,999 --> 99:59:59,999
almost --

12
99:59:59,999 --> 99:59:59,999
happens because of proteins.

13
99:59:59,999 --> 99:59:59,999
Proteins are linear chains
of building blocks called amino acids.

14
99:59:59,999 --> 99:59:59,999
Nature uses an alphabet
of 20 amino acids,

15
99:59:59,999 --> 99:59:59,999
some of which have names
you may have heard of.

16
99:59:59,999 --> 99:59:59,999
In this picture, for scale,
each bump is an atom.

17
99:59:59,999 --> 99:59:59,999
Chemical forces between the amino acids
cause these long stringy molecules

18
99:59:59,999 --> 99:59:59,999
to fold up into unique,
three-dimensional structures.

19
99:59:59,999 --> 99:59:59,999
The folding process,

20
99:59:59,999 --> 99:59:59,999
while it looks random,

21
99:59:59,999 --> 99:59:59,999
it is in fact very precise.

22
99:59:59,999 --> 99:59:59,999
Each protein folds to its characteristic
shape each time,

23
99:59:59,999 --> 99:59:59,999
and the folding process takes just
a fraction of a second.

24
99:59:59,999 --> 99:59:59,999
And it's the shapes of proteins

25
99:59:59,999 --> 99:59:59,999
which enable them to carry out
their remarkable biological functions.

26
99:59:59,999 --> 99:59:59,999
For example,

27
99:59:59,999 --> 99:59:59,999
hemoglobin has a shape
in the lungs perfectly suited

28
99:59:59,999 --> 99:59:59,999
for binding a molecule of oxygen.

29
99:59:59,999 --> 99:59:59,999
When hemoglobin moves to your muscle,

30
99:59:59,999 --> 99:59:59,999
the shape changes slightly

31
99:59:59,999 --> 99:59:59,999
and the oxygen comes out.

32
99:59:59,999 --> 99:59:59,999
The shapes of proteins,

33
99:59:59,999 --> 99:59:59,999
and hence their remarkable functions,

34
99:59:59,999 --> 99:59:59,999
are completely specified by the sequence
of amino acids in the protein chain.

35
99:59:59,999 --> 99:59:59,999
In this picture, each letter on top
is an amino acide.

36
99:59:59,999 --> 99:59:59,999
Where do these sequences come from?

37
99:59:59,999 --> 99:59:59,999
The genes in your genome 
specify the amino acid sequences

38
99:59:59,999 --> 99:59:59,999
of your proteins.

39
99:59:59,999 --> 99:59:59,999
Each gene encodes the amino acid
sequence of a single protein.

40
99:59:59,999 --> 99:59:59,999
The translation between these amino
acid sequences and the structures

41
99:59:59,999 --> 99:59:59,999
and funcions of proteins

42
99:59:59,999 --> 99:59:59,999
is known as the protein-folding problem.

43
99:59:59,999 --> 99:59:59,999
It's a very hard problem

44
99:59:59,999 --> 99:59:59,999
because there's so many different
shape a protein can adopt.

45
99:59:59,999 --> 99:59:59,999
Because of this complexity,

46
99:59:59,999 --> 99:59:59,999
humans have only been able
to harness the power of proteins

47
99:59:59,999 --> 99:59:59,999
by making very small changes
to the amino acid sequences

48
99:59:59,999 --> 99:59:59,999
of the proteins we found in nature.

49
99:59:59,999 --> 99:59:59,999
This is similar to the process
that our Stone Age ancestors used

50
99:59:59,999 --> 99:59:59,999
to make tools and other implements
from the sticks and stones

51
99:59:59,999 --> 99:59:59,999
that we found in the world around us.

52
99:59:59,999 --> 99:59:59,999
But humans did not learn to fly
by modifying birds.

53
99:59:59,999 --> 99:59:59,999
(Laughter)

54
99:59:59,999 --> 99:59:59,999
Instead, scientists inspired by birds,
uncovered the principles of aerodynamics.

55
99:59:59,999 --> 99:59:59,999
Engineers then used those principles
to design custom flying machines.

56
99:59:59,999 --> 99:59:59,999
In a similar way,

57
99:59:59,999 --> 99:59:59,999
we've been working for a number of years

58
99:59:59,999 --> 99:59:59,999
to uncover the fundamental principles
of protein folding

59
99:59:59,999 --> 99:59:59,999
and encoding those principles
in the computer program called "Rosetta."

60
99:59:59,999 --> 99:59:59,999
We made a breakthrough in recent years.

61
99:59:59,999 --> 99:59:59,999
We can now design completely new proteins
from scratch on the computer.

62
99:59:59,999 --> 99:59:59,999
Once we've designed the new protein,

63
99:59:59,999 --> 99:59:59,999
we encode its amino acid sequence
in a synthetic gene.

64
99:59:59,999 --> 99:59:59,999
We have to make a synthetic gene

65
99:59:59,999 --> 99:59:59,999
because since the protein
is completely new,

66
99:59:59,999 --> 99:59:59,999
there's no gene in any organism on earth
which currently exists that encodes it.

67
99:59:59,999 --> 99:59:59,999
Our advances in understanding
protein folding

68
99:59:59,999 --> 99:59:59,999
and how to design proteins,

69
99:59:59,999 --> 99:59:59,999
coupled with the decreasing cost
of gene synthesis

70
99:59:59,999 --> 99:59:59,999
and the More's Law increase
in computer power,

71
99:59:59,999 --> 99:59:59,999
now enable us to design tens
of thousands of new proteins

72
99:59:59,999 --> 99:59:59,999
with new shapes and new functions
on the computer,

73
99:59:59,999 --> 99:59:59,999
and encode each one of those
in a synthetic gene.

74
99:59:59,999 --> 99:59:59,999
Once we have those synthetic genes,

75
99:59:59,999 --> 99:59:59,999
we put them into bacteria

76
99:59:59,999 --> 99:59:59,999
to program them to make
these brand new proteins.

77
99:59:59,999 --> 99:59:59,999
We then extract the proteins

78
99:59:59,999 --> 99:59:59,999
and determine whether they function
as we designed them to do

79
99:59:59,999 --> 99:59:59,999
and whether they're safe.

80
99:59:59,999 --> 99:59:59,999
It's exciting to be able
to make new proteins

81
99:59:59,999 --> 99:59:59,999
because despite the diversity in nature,

82
99:59:59,999 --> 99:59:59,999
evolution has only sampled a tiny fraction
of the total number of proteins possible.

83
99:59:59,999 --> 99:59:59,999
I told you that nature uses
an alphabet of 20 amino acids,

84
99:59:59,999 --> 99:59:59,999
and a typical protein is a chain
of about 100 amino acids,

85
99:59:59,999 --> 99:59:59,999
so the total number of possibilities
is 20 times 20 times 20, 100 times,

86
99:59:59,999 --> 99:59:59,999
which is a number on the order
of 10 to the 130th power,

87
99:59:59,999 --> 99:59:59,999
which is enormously more
than the total number of proteins

88
99:59:59,999 --> 99:59:59,999
which have existed
since life on earth began.

89
99:59:59,999 --> 99:59:59,999
And it's this unimaginably large space
we can now explore

90
99:59:59,999 --> 99:59:59,999
using computational protein design.

91
99:59:59,999 --> 99:59:59,999
Now the proteins that exist on earth


92
99:59:59,999 --> 99:59:59,999
evolved to solve the problems
faced by natural evolution.

93
99:59:59,999 --> 99:59:59,999
For example, replicating the genome.

94
99:59:59,999 --> 99:59:59,999
But we face new challenges today.

95
99:59:59,999 --> 99:59:59,999
We live longer, so new
diseases are important.

96
99:59:59,999 --> 99:59:59,999
We're heating up and polluting the planet,

97
99:59:59,999 --> 99:59:59,999
so we face a full host
of ecological challenges.

98
99:59:59,999 --> 99:59:59,999
If we had a million years to wait,

99
99:59:59,999 --> 99:59:59,999
new proteins might evolve
to solve those challenges.

100
99:59:59,999 --> 99:59:59,999
But we don't have
millions of years to wait.

101
99:59:59,999 --> 99:59:59,999
Instead, with computational
protein design,

102
99:59:59,999 --> 99:59:59,999
we can design new proteins
to address these challenges today.

103
99:59:59,999 --> 99:59:59,999
Our audacious idea is to bring
biology out of the Stone Age

104
99:59:59,999 --> 99:59:59,999
through technological revolution
in protein design.

105
99:59:59,999 --> 99:59:59,999
We've already shown
that we can design new proteins

106
99:59:59,999 --> 99:59:59,999
with new shapes and functions.

107
99:59:59,999 --> 99:59:59,999
For example, vaccines work
my stimulating your immune system

108
99:59:59,999 --> 99:59:59,999
to make a strong response
against a pathogen.

109
99:59:59,999 --> 99:59:59,999
To make better vaccines,

110
99:59:59,999 --> 99:59:59,999
we've designed protein particles

111
99:59:59,999 --> 99:59:59,999
to which we confuse
proteins from pathogens,

112
99:59:59,999 --> 99:59:59,999
like this blue protein here
from the respiratory virus RSV.

113
99:59:59,999 --> 99:59:59,999
To make vaccine candidates

114
99:59:59,999 --> 99:59:59,999
that are literally bristling
with the viral protein,

115
99:59:59,999 --> 99:59:59,999
we find that such vaccine candidates

116
99:59:59,999 --> 99:59:59,999
produce a much stronger
immune response to the virus

117
99:59:59,999 --> 99:59:59,999
than any previous vaccines
that have been tested.

118
99:59:59,999 --> 99:59:59,999
This is important because RSV
is currently one of the leading causes

119
99:59:59,999 --> 99:59:59,999
of infant mortality worldwide.

120
99:59:59,999 --> 99:59:59,999
We've also designed new proteins
to break down gluten in your stomach

121
99:59:59,999 --> 99:59:59,999
for Celiac's Disease,

122
99:59:59,999 --> 99:59:59,999
and other proteins to stimulate
your immune system to fight cancer.

123
99:59:59,999 --> 99:59:59,999
These advances are the beginning
of the protein-design revolution.

124
99:59:59,999 --> 99:59:59,999
We've been inspired by a precious
technological revolution:

125
99:59:59,999 --> 99:59:59,999
the Digital Revolution,

126
99:59:59,999 --> 99:59:59,999
which took place in large part
due to advances in one place --

127
99:59:59,999 --> 99:59:59,999
Bell Laboratories.

128
99:59:59,999 --> 99:59:59,999
The Labs was a place with an open,
collaborative environment

129
99:59:59,999 --> 99:59:59,999
and was able to attract top talent
from around the world.

130
99:59:59,999 --> 99:59:59,999
And this led to a remarkable
string of innovations --

131
99:59:59,999 --> 99:59:59,999
the transistor,

132
99:59:59,999 --> 99:59:59,999
the laser,

133
99:59:59,999 --> 99:59:59,999
satellite communication

134
99:59:59,999 --> 99:59:59,999
and the foundations of the internet.

135
99:59:59,999 --> 99:59:59,999
Our goal is to build
the Bell Laboratories of protein design.

136
99:59:59,999 --> 99:59:59,999
We are seeking to attract
talented scientists from around the world

137
99:59:59,999 --> 99:59:59,999
to accelerate the protein
design revolution,

138
99:59:59,999 --> 99:59:59,999
and we'll be focusing on five
grand challenges.

139
99:59:59,999 --> 99:59:59,999
First, by taking proteins from flu strains
from around the world

140
99:59:59,999 --> 99:59:59,999
and putting them on top
of the design protein particles

141
99:59:59,999 --> 99:59:59,999
I showed you earlier,

142
99:59:59,999 --> 99:59:59,999
we aim to make a universal flu vaccine,

143
99:59:59,999 --> 99:59:59,999
one shot of which gives a lifetime
of protection against the flu.

144
99:59:59,999 --> 99:59:59,999
The ability to design --

145
99:59:59,999 --> 99:59:59,999
(Applause)

146
99:59:59,999 --> 99:59:59,999
The ability to design
new vaccines on the computer

147
99:59:59,999 --> 99:59:59,999
is important both to protecting
against natural flu epidemics

148
99:59:59,999 --> 99:59:59,999
and in addition, intentional
acts of bioterrorism.

149
99:59:59,999 --> 99:59:59,999
Second, we're going far beyond
nature's limited alphabet

150
99:59:59,999 --> 99:59:59,999
of just 20 amino acids

151
99:59:59,999 --> 99:59:59,999
to design new therapeutic candidates
for conditions such a chronic pain,

152
99:59:59,999 --> 99:59:59,999
using an alphabet
of thousands of amino acids.

153
99:59:59,999 --> 99:59:59,999
Third, we're building
advanced delivery vehicles

154
99:59:59,999 --> 99:59:59,999
to targe existing medications
exactly where they need to go in the body.

155
99:59:59,999 --> 99:59:59,999
For example, chemotherapy to a tumor

156
99:59:59,999 --> 99:59:59,999
or gene therapies to the tissue
where gene repair needs to take place.

157
99:59:59,999 --> 99:59:59,999
Fourth, we're designing smart therapeutics
that can do calculations within the body

158
99:59:59,999 --> 99:59:59,999
and go far beyond current medicines,

159
99:59:59,999 --> 99:59:59,999
which are really blunt instruments.

160
99:59:59,999 --> 99:59:59,999
For example, to target a small
subset of immune cells

161
99:59:59,999 --> 99:59:59,999
responsible for an autoimmune disorder

162
99:59:59,999 --> 99:59:59,999
and distinguish them from the vast
majority of healthy immune cells.

163
99:59:59,999 --> 99:59:59,999
Finally, inspired by remarkable
biological materials

164
99:59:59,999 --> 99:59:59,999
such as silk, Abalone shell,
tooth and others,

165
99:59:59,999 --> 99:59:59,999
we're designing new protein-based material
to address challenges in energy

166
99:59:59,999 --> 99:59:59,999
and ecological issues.

167
99:59:59,999 --> 99:59:59,999
To do all this,

168
99:59:59,999 --> 99:59:59,999
we're growing our institute.

169
99:59:59,999 --> 99:59:59,999
We seek to attract energetic, talented
and diverse scientists

170
99:59:59,999 --> 99:59:59,999
from around the world

171
99:59:59,999 --> 99:59:59,999
at all carreer stages,

172
99:59:59,999 --> 99:59:59,999
to join us.

173
99:59:59,999 --> 99:59:59,999
You can also participate
in the protein design revolution

174
99:59:59,999 --> 99:59:59,999
through our online folding game,

175
99:59:59,999 --> 99:59:59,999
folding and design game, "Foldit."

176
99:59:59,999 --> 99:59:59,999
And through our distributed
computing project, Rosetta@home,

177
99:59:59,999 --> 99:59:59,999
which you can join from your laptop
or your Android smartphone.

178
99:59:59,999 --> 99:59:59,999
Making the world a better place
through protein design is my life's work.

179
99:59:59,999 --> 99:59:59,999
I'm so excited about
what we can do together.

180
99:59:59,999 --> 99:59:59,999
I hope you'll join us,

181
99:59:59,999 --> 99:59:59,999
and thank you.

182
99:59:59,999 --> 99:59:59,999
(Applause and cheers)