Class 5 October 9 2020 BuildaGenome Course 2020 Synthetic Genomes Existing Currently Zhang et al Annu Rev Biochem 2020 8977101 Human Genome Project HGP Read HGP initiated by the International Human Genome Sequencing Consortium consisting of gt2800 scientists from 20 ID: 916514
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Slide1
Synthetic Human Genome
Dhiman PalClass 5October 9, 2020Build-a-Genome Course 2020
Slide2Synthetic Genomes Existing Currently
Zhang et al Annu. Rev. Biochem. 2020. 89:77–101
Slide3Human Genome Project (HGP) - Read
HGP initiated by the International Human Genome Sequencing Consortium consisting of >2,800 scientists from 20 institutions globally
Started in October 1990, and finished in April 2003
Total cost ~ $ 2.7 billion
DNA collected from blood samples of volunteers
Human chromosomes range in size from about 50-300 million base pairs
Chromosomes broken into fragments, cloned into bacterial artificial chromosomes, & sequenced
HGP has revealed that there are ~20,500 human genes
HGP gave us the ability, for the first time, to read nature's complete genetic blueprint for building a human being
https://www.genome.gov/
Slide4Benefits of Human Genome Project (HGP)-Read
Enhance knowledge of human genome (such as how many protein-coding genes are present?)Enhance existing technology such as DNA sequencing
Finishing the euchromatic sequence of the human genome.
Nature
431,
931–945 (2004).
Slide5Reading
the Human GenomeWriting the Human Genome
HGP-Read vs HGP-Write
The New York Times: Andrew Pollack, May 13, 2016
Slide6https://engineeringbiologycenter.org/ultrasafecells/
Complexity of Synthetic Genomes over the Years
Slide71. Responsible Innovation
HGP-write will require public involvement and consideration of ethical, legal, and social implications (ELSI) from the start
Broad public discourse on HGP-write: Hold conversations well in advance of project implementation will guide emerging capabilities in science and contribute to societal decision-making
2
. From Observation to Action
P
rimary goal of HGP-write is to reduce the costs of engineering and testing large genomes in cell lines to 1/1000th of previous efforts within 10 years.
This will include whole-genome engineering of human cell lines and other organisms of agricultural and public health significance or those needed to interpret human biological functions—i.e., gene regulation, genetic diseases, and evolutionary processes
Human Genome Project-Write
The primary goal “would be to synthesize a complete human genome in a cell line within a period of 10 years.”
Slide8The Primary
Goal “would be to synthesize a complete human genome in a cell line within a period of 10 years.”
Slide9Challenges for
Building Mammalian Synthetic C
hromosomes
1.
Handling DNA
in
vitro
3.
Nuclear delivery
4.
Site-specific
Integra
ti
on
2.
Intact
transfer
5.
Fitness/func
ti
on
One of the challenges of making this project work is getting the completed genome, or part of the genome, into a host cell. This host could be a mammalian cell or a bacteria like
E. coli
.
Slide10Challenges for
Building Mammalian Synthetic
C
hromosomes
Boeke
, Church,
et al Science
Vol 356 (2016)
“The overall cost for the HGP-write project will likely be huge, but the group expects it to cost less than the $3 billion spent on the first Human Genome Project”
- Prof Francis Collins, NIH
Slide11Genome
Writing
P
ipeline
What are you going to
build…and
WHY?
A
grand
challenge…or a grant challenge?It’s going to be a big job, who will participate?
What is the defini
ti
on
of
success?
Idea
De
si
gn
Source
DNA
Build
Measure
&
Debug
Deliver
Slide12https://engineeringbiologycenter.org/ultrasafecells/
Priority Shift in 2018…
Synthesizing
Complete Human Genome
Recoding
Existing Human Genome
Slide13Proof of Concept : Recoding Bacterial Genome to Confer Viral Immunity
https://engineeringbiologycenter.org/ultrasafecells/
Slide14https://engineeringbiologycenter.org/ultrasafecells/
Benefits of Synthetic Human Genomes: Creation of Ultra-Safe Cell lines
Boeke
, Church,
et al Science
Vol 356 (2016)
Slide15Ethical Dilemmas of Synthesizing Human Genomes
Could scientists create humans with certain kinds of traits, perhaps people born and bred to be soldiers? Or might it be possible to make copies of specific people ?“The project was not aimed at creating people, just cells, and would not be restricted to human genomes.
Rather it would aim to improve the ability to synthesize DNA in general, which could be applied to various animals, plants and microbes.”
- Prof. George Church,
Harvard
Medical School
S
cientists will create a new race of superhumans ?
“…cells containing a synthetic genome would be designed so if one is ever grown into a full human, it won’t be able to reproduce. We’re not trying to make an army of clones or start a new era of eugenics,”- Prof.
Jef
Boeke, NYU Langone