Genome
engineering just went from a meticulous step by step replacement and test out
process to taking a deck of cards and throwing them in the air and using the
results to sort out meaning. Thus is
obviously faster and plausibly more efficient and actually imitates what nature
does itself somehow. What I find most
promising is the sheer capacity to produce ample data fast.
I was cringing
at the DNA decoding problem facing science and could only foresee years of
scientific drudgery. It is going to turn
out a lot easier with all the heavy lifting done by computers. That all means massive results in as little
as ten years.
Add in the
developing Genome of at least one alien species if not two or more and we will
also have our own Rosetta stone to assist us in understanding it all. Thus we are going to master the whole genome
and our options inside perhaps fifty years or the lifetimes of the thousands of
genome scientists now been minted.
‘Built from
scratch’ chromosome takes us one step closer to synthetic life
Creating fully-artificial life forms, plants,
animals and even microorganisms 'from scratch' has largely been something left
to the pages of science fiction, but an international team of scientists has
taken us one step closer to pulling that idea off the page and putting it into
real, practical use.
The team, led by New York University geneticist Jef
Boeke, is reporting that they've made the first fully functional
'designer' chromosome — the snippets of DNA that carry genetic
information — from the DNA of common brewers yeast. Although previous studies
have produced synthetic versions of virus DNA and bacterial chromosomes, this
is the first time that scientists have done so for aeukaryotic organism
(plants, animals and fungi).
This 'scrambling' technique that Dr. Boeke describes
basically treats the chromosome as a deck of cards, with each gene in the
chromosome treated as an individual card.
"We can pull together any group of cards,
shuffle the order and make millions and millions of different decks, all in one
small tube of yeast," Dr. Boeke said in an NYU news release. "Now that we can shuffle the genomic deck, it
will allow us to ask, can we make a deck of cards with a better hand for making
yeast survive under any of a multitude of conditions, such as tolerating higher
alcohol levels."
Not only that, but this kind of shuffling technique
could lead to other advances in genetics and biology, to produce medications
and vaccines and even better biofuels.
This global synthetic yeast genome project, called
Sc2.0, involves researchers and undergraduate students from nearly a dozen
different institutions in five different nations around the world, and their research
is detailed on their website, syntheticyeast.org.
Scientists
Synthesize First Functional “Designer” Chromosome in Yeast
Study reports major advance in synthetic biology
March 27, 2014 (All day)
An international team of scientists led by Jef Boeke, PhD, director of
NYU Langone Medical Center’s Institute
for Systems Genetics, has
synthesized the first functional chromosome in yeast, an important step in the
emerging field of synthetic biology, designing microorganisms to produce novel
medicines, raw materials for food, and biofuels.
Over the last five years, scientists have built
bacterial chromosomes and viral DNA, but this is the first report of an entire
eukaryotic chromosome, the threadlike structure that carries genes in the
nucleus of all plant and animal cells, built from scratch. Researchers say
their team’s global effort also marks one of the most significant advances in
yeast genetics since 1996, when scientists initially mapped out yeast’s entire
DNA code, or genetic blueprint.
“Our research moves the needle in synthetic biology
from theory to reality,” says Dr. Boeke, a pioneer in synthetic biology who
recently joined NYU Langone from Johns Hopkins University.
“This work represents the biggest step yet in an
international effort to construct the full genome of synthetic yeast,” says Dr.
Boeke. “It is the most extensively altered chromosome ever built. But the
milestone that really counts is integrating it into a living yeast cell. We
have shown that yeast cells carrying this synthetic chromosome are remarkably
normal. They behave almost identically to wild yeast cells, only they now
possess new capabilities and can do things that wild yeast cannot.”
In this week’s issue of Science online
March 27, the team reports how, using computer-aided design, they built a fully
functioning chromosome, which they call synIII, and successfully incorporated
it into brewer’s yeast, known scientifically as Saccharomyces cerevisiae.
The seven-year effort to construct synIII tied
together some 273, 871 base pairs of DNA, shorter than its native yeast
counterpart, which has 316,667 base pairs. Dr. Boeke and his team made more
than 500 alterations to its genetic base, removing repeating sections of some
47,841 DNA base pairs, deemed unnecessary to chromosome reproduction and
growth. Also removed was what is popularly termed junk DNA, including base
pairs known not to encode for any particular proteins, and “jumping gene”
segments known to randomly move around and introduce mutations. Other sets of
base pairs were added or altered to enable researchers to tag DNA as synthetic
or native, and to delete or move genes on synIII.
“When you change the genome you’re gambling. One
wrong change can kill the cell,” says Dr. Boeke. “We have made over 50,000
changes to the DNA code in the chromosome and our yeast still live. That is
remarkable. It shows that our synthetic chromosome is hardy, and it endows the
yeast with new properties.”
The Herculean effort was aided by some 60
undergraduate students enrolled in the “Build a Genome” project, founded by Dr.
Boeke at Johns Hopkins. The students pieced together short snippets of the
synthetic DNA into stretches of 750 to 1,000 base pairs or more. These pieces
were then assembled into larger ones, which were swapped for native yeast DNA, an
effort led by Srinivasan Chandrasegaran, PhD, a professor at Johns Hopkins.
Chandrasegaran is also the senior investigator of the team’s studies on synIII.
Student participation kicked off what has become an
international effort, called Sc2.0 for short, in which several academic
researchers have partnered to reconstruct the entire yeast genome, including
collaborators at universities in China, Australia, Singapore, the United
Kingdom, and elsewhere in the U.S.
Yeast chromosome III was selected for synthesis
because it is among the smallest of the 16 yeast chromosomes and controls how
yeast cells mate and undergo genetic change. DNA comprises four
letter-designated base macromolecules strung together in matching sets, or base
pairs, in a pattern of repeating letters. “A” stands for adenine, paired with
“T” for thymine; and “C” represents cysteine, paired with “G” for guanine. When
stacked, these base pairs form a helical structure of DNA resembling a twisted
ladder.
Yeast shares roughly a third of its 6,000
genes—functional units of chromosomal DNA for encoding proteins — with humans.
The team was able to manipulate large sections of yeast DNA without
compromising chromosomal viability and function using a so-called scrambling
technique that allowed the scientists to shuffle genes like a deck of cards,
where each gene is a card. “We can pull together any group of cards, shuffle
the order and make millions and millions of different decks, all in one small
tube of yeast,” Dr. Boeke says. “Now that we can shuffle the genomic deck, it
will allow us to ask, can we make a deck of cards with a better hand for making
yeast survive under any of a multitude of conditions, such as tolerating higher
alcohol levels.”
Using the scrambling technique, researchers say they
will be able to more quickly develop synthetic strains of yeast that could be
used in the manufacture of rare medicines, such as artemisinin for malaria, or
in the production of certain vaccines, including the vaccine for hepatitis B,
which is derived from yeast. Synthetic yeast, they say, could also be used to
bolster development of more efficient biofuels, such as alcohol, butanol, and
biodiesel.
The study will also likely spur laboratory
investigations into specific gene function and interactions between genes, adds
Dr. Boeke, in an effort to understand how whole networks of genes specify
individual biological behaviors.
Their initial success rebuilding a functioning
chromosome will likely lead to the construction of other yeast chromosomes
(yeast has a total of 16 chromosomes, compared to humans’ 23 pairs), and move
genetic research one step closer to constructing the organism’s entire
functioning genome, says Dr. Boeke.
Dr. Boeke says the international team’s next steps
involve synthesizing larger yeast chromosomes, faster and cheaper. His team,
with further support from Build a Genome students, is already working on
assembling base pairs in chunks of more than 10,000 base pairs. They also plan
studies of synIII where they scramble the chromosome, removing, duplicating, or
changing gene order.
Detailing the Landmark Research Process
Before testing the scrambling technique, researchers
first assessed synIII’s reproductive fitness, comparing its growth and
viability in its unscrambled from — from a single cell to a colony of
many cells — with that of native yeast III. Yeast proliferation was gauged
under 19 different environmental conditions, including changes in temperature,
acidity, and hydrogen peroxide, a DNA-damaging chemical. Growth rates remained
the same for all but one condition.
Further tests of unscrambled synIII, involving some
30 different colonies after 125 cell divisions, showed that its genetic
structure remained intact as it reproduced. According to Dr. Boeke, individual
chromosome loss of one in a million cell divisions is normal as cells divide.
Chromosome loss rates for synIII were only marginally higher than for native
yeast III.
To test the scrambling technique, researchers
successfully converted a non-mating cell with synIII to a cell that could mate
by eliminating the gene that prevented it from mating.
Funding support for these experiments was provided
by National Science Foundation, the National Institutes of Health, and
Microsoft. Corresponding federal grant numbers are MCB-0718846 and GM-077291.
Additional funding support was provided by fellowships from La Fondation pour
la Recherche Médicale, Pasteur-Roux, National Sciences and Engineering Research
Council of Canada, U.S. Department of Energy, and grants from the Exploratory
Research Grant from the Maryland Stem Cell Research Fund and the Johns Hopkins
University Applied Physics Laboratory.
Besides the teams at NYU Langone and Johns Hopkins,
other scientific teams involved in the global Sc2.0 research effort are based
at Loyola University in Baltimore, Md; BGI in Shenzhen, China; Tianjin
University in China; Tsinghua University in China; MacQuarie University in
Sydney, Australia; the Australian Wine Institute in Adelaide, Australia; the
National University of Singapore; Imperial College, London, England; and the
University of Edinburgh in Scotland.
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