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EACH YEAR, Technology Reviewidentifes 10 technologies that are worth keeping
an eye on. This years list spans a broad range o disciplines, rom lie sciences to
nanotechnology to the Internet, but the technologies have one thing in common:
they will soon have a signifcant impact on business, medicine,
or culture.Nanomedicineandnanobiomechanicsboth illustrate
nanotechnologys increasing contribution to the understanding
and treatment o diseases. In biology, epigeneticsis part o an
exploding eort to understand the ways that chemical com-
pounds can inuence DNA, while comparative interactomics
is a compelling example o how researchers are beginning to
visualize the bodys remarkable complexity.Diffusion tensorimagingis the most recent in a series o astonishing break-
throughs in imaging the brain. Meanwhile, cognitive radio,
pervasive wireless,and universal authenticationreect the continuing struggle to
keep the digital world accessible and secure. There is also controversy on the list:
nuclear reprogrammingdescribes the contentious hunt or an ethical stem cell.
Finally, some o the technologies, such as stretchable silicon, are just cool.
TechnologyReview
10EmergingTechnologies
Comparative interactomics. . . . 5
Nanomedicine . . . . . . . . . . . . . . . . . 58
Epigenetics . . . . . . . . . . . . . . . . . . . . 59
Cognitive radio . . . . . . . . . . . . . . . . 1
Nuclear reprogramming . . . . . . .
Diffusion tensor imaging . . . . . . 4
Universal authentication . . . . . . 5
Nanobiomechanics. . . . . . . . . . . . 7
Pervasive wireless . . . . . . . . . . . . . 8Stretchable silicon. . . . . . . . . . . . . 7
BRYANC
H
RISTIED
ESIG
N
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BIOMEDICAL RESEARCH THE SE DAYS
seems to be all about the omes:
genomes, proteomes, metabolomes.
Beyond all these lies the mother o
all omesor maybe just the ome du
jour: the interactome. Every cell hosts avast array o interactions among genes,RNA, metabolites, and proteins. The
impossibly complex map o all these
interactions is, in the language o sys-tems biology, the interactome.
Trey Ideker, a molecular biotech-
nologist by way o electrical engineer-
ing, has recently begun comparing
what he calls the circuitry o the
interactomes o dierent species. Its
really an incremental step in terms o
the concepts, but its a major leap or-
ward in that we can gather and analyzecompletely new types o inormation
to characterize biological systems,
says Ideker, who runs the Laboratory
or Integrative Network Biology at theUniversity o Caliornia, San Diego. Ithink its going to be cool to map out
the circuitry o all these cells.
Beyond the cool actor, Ideker and
other leaders in the nascent feld o
interactomics hope that their work mayhelp uncover new drugs, improve exist-ing drugs by providing a better under-
standing o how they work, and even
lead to computerized models o toxi-
city that could replace studies now con-ducted on animals. Disease and drugs
are about pathways, Ideker says.Ideker made a big splash in the feld
in 2001 while still a graduate student
with Leroy Hood at the Institute or
Systems Biology in Seattle. In a paper
orScience, Ideker, Hood, and cowork-
ers described in startling detail how
yeast cells use sugar. They presented a
wiring-like diagram illustrating every-
thing rom the suite o genes involved, tothe protein-protein interactions, to how
perturbing the system altered dierent
biochemical pathways. His contributionwas really special, says geneticist Marc
Vidal o the Dana-Farber Cancer Insti-
tute in Boston, who introduced the con-cept that interactomes can be conservedbetween species. He came up with one
o the frst good visualization tools.Last November, Idekers team
turned heads by reporting inNature
that it had aggregated in one database
all the available protein-protein inter-
actomes o yeast, the ruit y, the nema-tode worm, and the malaria-causing
parasite Plasmodium falciparum.
Though theres nothing particularly
novel about comparing proteins across
species, Idekers lab is one o the ew
that has begun hunting or similarities
and dierences between the protein-
protein interactionso widely dierentcreatures. It turns out that the interac-
tomes o yeast, y, and worm include
interactions called protein complexes
that have some similarities between
them. This conservation across speciesindicates that the interactions may servesome vital purpose. But Plasmodium,
oddly, shares no protein complexes withworm or y and only three with yeast.
For a while, we struggled to fgure outwhat was going wrong with our analy-sis, says Ideker. Ater rechecking theirdata, Ideker and his team concluded
that Plasmodiumprobably just had asomewhat dierent interactome.
For pharmaceutical makers, the dis-covery o unique biological pathways,
such as those ound in the malaria
parasite, suggests new drug targets.
Theoretically, a drug that can interruptsuch a pathway will have limited, i
any, impact on circuits in human cells,reducing the likelihood o toxic side
eects. Theoretically. In reality, phar-
maceutical companies arent exactly
tripping over themselves to make
new drugs or malariaa disease thatstrikes mainly in poor countries. But
the general idea has great promise,
says Ideker, who now plans to com-
pare the interactomes o dierent HIVstrains to see whether any chinks in
that viruss armor come to light.
George Church, who directs the
Lipper Center or Computational
Genetics at Harvard Medical School,
has high respect or Ideker but adds
another caveat: existing interactome
data comes rom ast, automated tests
that simply arent that accurate yet.The way I divide the omes is by ask-
ing, Are these data permanent, or are
they going to be replaced by somethingbetter? says Church. Data on the
DNA sequences o genomes, Church
says, is permanent. But interactome
data? Theres a 50-50 chance that thiswill be true or accepted in two years,
says Church. Thats not Treys ault.
Hes one o the people who is trying
to make it more rigorous.
Ideker agrees that theres a lot o
noise in the system, but he says thecontinuing ood o interactome data is
making what happens inside dierent
cells ever more clear. Within fve years,we hope to take these interaction data
and build models o cellular circuitry topredict actions o drugs beore theyre
in human trials. Thats the billion-dollarapplication. JON COHEN
DRUG DISCOVERY
Comparative InteractomicsBy etng s of te bodys oex oeu nte-tons, Tey Ideke s ovdng new wys to find dugs.
OTHER PLAYERSComparative Interactomics
Resee PojetJames Collins Syntet geneBoston University netwoks
Bernhard Palsson MetboUniversity of California, netwoksSan Diego
Marc Vidal Coson ofDana-Farber Cancer ntetoesInstitute, Boston, MA ong sees
GREGGSEGAL
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Trey Ideker
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THE TREATMENT BEGINS WITH AN
injection o an unremarkable-looking
clear uid. Invisible inside, however,are particles precisely engineered to
slip past barriers such as blood ves-
sel walls, latch onto cancer cells, and
trick the cells into engulfng them as
i they were ood. These Trojan par-
ticles ag the cells with a uorescent
dye and simultaneously destroy them
with a drug.
Developed by University o Michiganphysician and researcher James Baker,these multipurpose nanoparticles
which should be ready or patient
trials later this yearare at the lead-ing edge o a nanotechnology-based
medical revolution. Such methodicallydesigned nanoparticles have the poten-tial to transfgure the diagnosis and
treatment o not only cancer but virtu-ally any disease. Already, researchers
are working on inexpensive tests that
could distinguish a case o the sni es
rom the early symptoms o a bioterrorattack, as well as treatments or disor-
ders ranging rom rheumatoid arthritisto cystic fbrosis. The molecular fnesseo nanotechnology, Baker says, makesit possible to fnd things like tumor
cells or inammatory cells and get intothem and change them directly.
Cancer therapies may be the frst
nanomedicines to take o. Treatmentsthat deliver drugs to the neighbor-
hood o cancer cells in nanoscale cap-
sules have recently become available
or breast and ovarian cancers and or
Kaposis sarcoma. The next genera-
tion o treatments, not yet approved,improves the drugs by delivering theminside individual cancer cells. This gen-eration also boasts multiunction par-
ticles such as Bakers; in experiments
reported last June, Bakers particles
slowed and even killed human tumorsgrown in mice ar more e ciently thanconventional chemotherapy.
The feld is dramatically expand-
ing, says Piotr Grodzinski, program
director o the National Cancer Insti-
tutes Alliance or Nanotechnology in
Cancer. Its not an evolutionary tech-nology; its a disruptive technology thatcan address the problems which or-
mer approaches couldnt.
The heart o Bakers approach is
a highly branched molecule called a
dendrimer. Each dendrimer has morethan a hundred molecular hooks onits surace. To fve or six o these, Bakerconnects olic-acid molecules. Becauseolic acid is a vitamin, most cells in thebody have proteins on their suraces
that bind to it. But many cancer cells
have signifcantly more o these recep-tors than normal cells. Baker links an
anticancer drug to other branches
o the dendrimer; when cancer cells
ingest the olic acid, they consume thedeadly drugs as well.
The approach is versatile. Baker hasladen the dendrimers with moleculesthat glow under MRI scans, which can
reveal the location o a cancer. And he
can hook dierent targeting molecules
and drugs to the dendrimers to treat
a variety o tumors. He plans to begin
human trials later this year, potentially
on ovarian or head and neck cancer.
BRYANCH
RISTIEDESIG
N
THERAPEUTICS
NanomedicineJes Bke desgns nnotes to gude dugs detynto ne es, w oud ed to f sfe tetents.
MOLECULES LINKED to nnote bndto te sufe of ne e, tkng t ntongestng te nnote, ong wt notennote yng yod of ntnedug. Te tes e onneted by DNA
stnds, w n z togete dffeent ob-ntons of tes fo esonzed tetents.
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SEQUENCING THE HUMAN GENOME
was ar rom the last step in explaininghuman genetics. Researchers still needto fgure out which o the 20,000-plus
human genes are active in any one cellat a given moment. Chemical modifca-tions can interere with the machineryo protein manuacture, shutting genesdown directly or making chromosomes
hard to unwind. Such chemical inter-actions constitute a second order o
genetics known as epigenetics.
In the last fve years, researchers havedeveloped the frst practical tools or
identiying epigenetic interactions, andGerman biochemist Alexander Olek is
one o the trailblazers. In 1998, Olek
ounded Berlin-based Epigenomics to
create a rapid and sensitive test or genemethylation, a common DNA modi-
fcation linked to cancer. The compa-
nys orthcoming tests will determine
not only whether a patient has a cer-
tain cancer but also, in some cases, the
severity o the cancer and the likelihoodthat it will respond to a particular treat-ment. Alex has opened up a whole newway o doing diagnostics, says StephanBeck, a researcher at the Wellcome
Trust Sanger Institute in Cambridge,
England, and an epigenetics pioneer.Methylation adds our atoms to
cytosine, one o the our DNA let-
ters, or nucleotides. The body natu-
rally uses methylation to turn genes
on and o: the additional atoms blockthe proteins that transcribe genes. Butwhen something goes awry, methyla-
tion can unleash a tumor by silencing
a gene that normally keeps cell growthin check. Removing a genes natural
methylation can also render a cell can-
Mauro Ferrari, a proessor o inter-
nal medicine, engineering, and materi-als science at Ohio State University, is
hopeul about what Bakers work could
mean or cancer patients. What Jim isdoing is very important, he says. It ispart o the second wave o approaches
to targeted therapeutics, which I think
will have tremendous acceleration o
progress in the years to come.
To hasten development o nano-
based therapies, the NCI alliance has
committed $144.3 million to nanotech-related projects, unding seven centerso excellence or cancer nanotechnologyand 12 projects to develop diagnostics
and treatments, including Bakers.
Baker has already begun work on amodular system in which dendrimers
adorned with dierent drugs, imagingagents, or cancer-targeting molecules
could be zipped together. Ultimately,doctors might be able to create person-alized combinations o nanomedicinesby simply mixing the contents o vials
o dendrimers.
Such a system is at least 10 years
away rom routine use, but Bakers
basic design could be approved or usein patients in as little as fve years. That
kind o rapid progress is a huge parto what excites doctors and research-
ers about nanotechnologys medical
potential. It will completely revolu-
tionize large branches o medicine,
says Ferrari. KEVIN BULLIS
G
UNTERK
LOETZER/LAIF/REDUX
HUMAN GENETICS
EpigeneticsAexnde Oek s deveoed tests to detet neey by esung ts subte DNA nges.
OTHER PLAYERSNanomedicine
Resee Pojet
Raoul Kopelman Nnotes foUniversity of Michigan ne gng
nd tey
Robert Langer Nnote
MIT dug devey foostte ne
Charles Lieber Nnowe devesHarvard University fo vus dete-
ton nd neseenng
Ralph Weissleder Mgnet nno-Harvard University tes fo
ne gngAlexander Olek
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Heather Zheng
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GROWING NUMBERS OF PEOPLE ARE
making a habit o toting their laptops
into Starbucks, ordering hal-ca skim
lattes, and plunking down in chairs to
sur the Web wirelessly. That means
more people are also getting used to
being kicked o the Net as computerscompeting or bandwidth interere withone another. Its a local eectwithin 30to 60 meters o a transceiverbut theresjust no more space in the part o the
radio spectrum designated or Wi-Fi.
Imagine, then, what happens as
more devices go wirelessnot just lap-tops, or cell phones and BlackBerrys,
but sensor networks that monitor
everything rom temperature in o ce
buildings to moisture in cornfelds,
radio requency ID tags that track mer-
chandise at the local Wal-Mart, devicesthat monitor nursing-home patients.All these gadgets have to share a fniteand increasingly crowdedamount o
radio spectrum.
Heather Zheng, an assistant pro-
essor o computer science at the Uni-
versity o Caliornia, Santa Barbara,
is working on ways to allow wireless
devices to more e ciently share the
airwaves. The problem, she says, is
not a dearth o radio spectrum; its theway that spectrum is used. The Fed-
eral Communications Commission in
the United States, and its counterparts
around the world, allocate the radiospectrum in swaths o requency o
varying widths. One band covers AM
radio, another VHF television, still oth-ers cell phones, citizens-band radio,
pagers, and so on; now, just as wire-
less devices have begun prolierating,
theres little let over to dole out. But
as anyone who has twirled a radio dialknows, not every channel in every bandis always in use. In act, the FCC has
determined that, in some locations or
at some times o day, 70 percent o the
allocated spectrum may be sitting idle,even though its o cially spoken or.Zheng thinks the solution lies with
cognitive radios, devices that fgure
out which requencies are quiet and
pick one or more over which to trans-
mit and receive data. Without careul
planning, however, certain bands couldstill end up jammed. Zhengs answer
cerous by activating a gene that is typi-cally o in a particular tissue.
The problem is that methylated
genes are hard to recognize in their
native state. But Olek says Epigenom-ics has developed a method to detect aslittle as three picograms o methylated
DNA; it will spot as ew as three cancercells in a tissue sample.
To create a practical diagnostic test
or a given cancer, Epigenomics com-
pares several thousand genes rom
cancerous and healthy cells, identiy-
ing changes in the methylation o one
or more genes that correlate with the
disease. Ultimately, the test examines
the methylation states o only the rele-
vant genes. The researchers go evenurther through a sort o epigenetic
archeology: by examining the DNA intissues rom past clinical trials, they
can identiy the epigenetic signals in
the patients who responded best or
worst to a given treatment.
Philip Avner, an epigenetics pioneerat the Pasteur Institute in Paris, says
that Epigenomics test is a powerul toolor accurately diagnosing and under-
standing cancers at their earliest stages.I we cant prevent cancer, at least we
can treat it better, says Avner.Roche Diagnostics expects to bring
Epigenomics frst product, a screeningtest or colon cancer, to market in 2008.The test is several times more likely
to spot a tumor than the current test,
which measures the amount o blood
in a stool sample. And thanks to the
sensitivity o its process, Epigenomicscan detect the tiny amounts o methyl-ated DNA such tumors shed into the
bloodstream, so only a standard bloodsample is required. The company is
working on diagnostics or three morecancers: non-Hodgkins lymphoma,breast cancer, and prostate cancer.
Olek believes that epigenetics couldalso have applications in helping
explain how liestyle aects the aging
process. It might reveal, or example,
why some individuals have a propen-
sity toward diabetes or heart disease.
Oleks goal is a human-epigenome
mapping project that would identiy
the ull range o epigenetic variation
possible in the human genome. Such
a map, Olek believes, could reveal themissing links between genetics, disease,and the environment. Today, progress
on the methylation catalogue is accel-
erating, thanks to Epigenomics and theWellcome Trust Sanger Institute, whichpredict that the methylation status o 10percent o human genes will be mappedby the end o this year. PETER FAIRLEY
G
REGGS
EGAL
W I R E L E S S
Cognitive RadioTo vod futue weess tffi js, Hete Hto Zengs findng wys to exot unused do setu.
OTHER PLAYERSEpigenetics
Resee Pojet
Stephan Beck Egenets of
Wellcome Trust Sanger te uneInstitute, Cambridge, systeEngland
Joseph Bigley Cne dgnossOncoMethylome nd dug deve-Sciences, Durham, NC oent
Thomas Gingeras Gene sAffymetrix, fo egenetsSanta Clara, CA
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is to teach cognitive radios to negotiatewith other devices in their vicinity. In
Zhengs scheme, the FCC-designated
owner o the spectrum gets priority,
but other devices can divvy up unusedspectrum among themselves.
But negotiation between devices usesbandwidth in itsel, so Zheng simplifedthe process. She selected a set o rules
based on game theorya type o mathe-matical modeling oten used to fnd the
optimal solutions to economics prob-
lemsand designed sotware that madethe devices ollow those rules. Instead
o each radios having to tell its neigh-
bor what its doing, it simply observes itsneighbors to see i they are transmitting
and makes its own decisions.Zheng compares the scheme to a
drivers reacting to what she sees otherdrivers doing. I Im in a tra c lane
that is heavy, maybe its time or me toshit to another lane that is not so busy,she says. When shiting lanes, however,a driver needs to ollow rules that pre-vent her rom bumping into others.
Zheng has demonstrated her
approach in computer simulations and
is working toward testing it on actual
hardware. But putting spectrum-sharing
theory into practice will take engineer-ing work, rom designing the right
antennas to writing the sotware that
will run the cognitive radios, Zheng
EMBRYONIC STEM CELLS MAY SPARK
more vitriolic argument than any othertopic in modern science. ConservativeChristians aver that the cells genesis,
which requires destroying embryos,
should make any research using themtaboo. Many biologists believe that
the cells will help unlock the secrets
o devastating diseases such as Par-kinsons and multiple sclerosis, pro-
viding benefts that ar outweigh any
perceived ethical harm.
Markus Grompe, director o the
Oregon Stem Cell Center at Ore-
gon Health and Science University in
Portland, hopes to fnd a way around
the debate by producing cloned cells
that have all the properties o embry-
onic stem cellsbut dont come rom
embryos. His plan involves a variation
on the cloning procedure that pro-
duced Dolly the sheep. In the origi-nal procedure, scientists transerred thegenetic material rom an adult cell intoan egg stripped o its own DNA. The
eggs proteins reprogrammed the adultDNA, creating an embryo genetically
identical to the adult donor. Grompe
believes that by orcing the donor cell toproduce a protein called nanog, which
is ound only in embryonic stem cells,
beore its nucleus is transerred into theegg, he can alter the reprogramming
process so that it never results in an
embryo but instead yields a cell resem-bling an embryonic stem cell.
Grompes work is part o a growingeort to fnd alternative ways to cre-
ate cells with the versatility o embry-onic stem cells. Many scientists hope
to use proteins to directly reprogram,
say, skin cells to behave like stem cells.Others think smaller molecules may
do the trick; Scripps Research Insti-
tute chemist Peter Schultz has ound achemical that turns mouse muscle cellsinto cells able to orm at and bone
cells. And Harvard University biologistKevin Eggan believes it may be pos-
sible to create stem cells whose DNA
matches a specifc patients by using
existing stem cells stripped o theirDNA to reprogram adult cells.
Meanwhile, researchers have testedmethods or extracting stem cells with-out destroying viable embryos. Last all,MIT biologist Rudol Jaenisch and
graduate student Alexander Meissner
showed that by turning o a gene calledCDX2 in the nucleus o an adult cell
STEM CELLS
Nuclear ReprogrammingHong to esove te ebyon-ste-e debte, MkusGoe envsons oe et wy to deve te es.
OTHER PLAYERSCognitive Radio
Resee Pojet
Bob Broderson AdvnedUniversity of ountonCalifornia, Berkeley gots nd
ow-owedeves
John Chapin Softwe-defined
Vanu, Cambridge, MA dosMichael Honig Png gotNorthwestern University fo setu
sng
Joseph Mitola III Cogntve dosMitre, McLean, VA
Adam Wolisz Potoos foTechnical University ountonsof Berlin, Germany netwoks
acknowledges. This is just a starting
phase, she says.
Nonetheless, cognitive radios are
already making headway in the real
world. Intel has plans to build recon-fgurable chips that will use sotware toanalyze their environments and select
the best protocols and requencies or
data transmission. The FCC has made
special allowances so that new types o
wireless networks can test these ideas
on unused television channels, and the
Institute o Electrical and Electronics
Engineers, which sets many o the tech-nical standards that continue to drive the
Internet revolution, has begun consider-ing cognitive-radio standards. It may be10 years beore all the issues get sorted
out, Zheng says, but as the airwaves
become more crowded, all wireless
devices will need more e cient ways
to share the spectrum. NEIL SAVAGE
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beore transerring it into a nucleus-
ree egg cell, they could create a bio-
logical entity unable to develop into an
embryobut rom which they could stillderive normal embryonic stem cells.
Also last all, researchers at AdvancedCell Technology in Worcester, MA, grewembryonic stem cells using a technique
that resembles something called pre-implantation genetic diagnosis (PGD).
PGD is used to detect genetic abnormali-ties in embryos created through in vitroertilization; doctors remove a single cellrom an eight-cell embryo or testing.
Lanzas team separated single cells romeight-cell mouse embryos, but instead
o testing them, they put each in a sepa-
rate petri dish, along with embryonic
stem cells. Unidentifed actors caused
the single cells to divide and develop
some o the characteristics o stem cells.When the remaining seven-cell embryoswere implanted into emale mice, they
developed into normal mice.
Such methods, however, are unlikely
to resolve the ethical debate because,in the eyes o some, they still endangerembryos. Grompes approach holds outthe promise o unraveling the moral
dilemma. I it works, no embryo will
have been producedso no potential
lie will be harmed. As a result, some
conservative ethicists have endorsed
Grompes proposal.
Whether it is actually a easible
way to harvest embryonic stem cells
remains uncertain. Some are skep-
tical. Theres really no evidence it
would work, says Jaenisch. I doubt itwould. But the experiments Grompe
proposes, Jaenisch says, would still bescientifcally valuable in helping explainhow to reprogram cells to create stem
cells. Harvard Stem Cell Institute sci-
entist George Daley agrees. In act,
Daleys lab is also studying nanogs
ability to reprogram adult cells.
Still, many biologists and bioethi-
cists have mixed eelings about eorts
to reprogram adult cells to become plu-ripotent. While they agree the research
is important, they worry that raming itas a search or a stem cell compromisemay slow undingprivate and publicor embryonic-stem-cell research, ham-pering eorts to decipher or even curediseases that aect thousands o des-
perate people. Such delays, they argue,are a greater moral wrong than the losso cells that hold only the potential or
lie. Many ethicistsand the majority
o Americansseem to agree. Weve
already decided as a society that its
perectly okay to create and destroy
embryos to help inertile couples tohave babies. It seems incredible to me
that we could say that thats a legitimatething to do, but we cant do the same
thing to help fght diseases that kill
children, says David Magnus, direc-
tor o the Stanord Center or Biomedi-cal Ethics. ERIKA JONIETZ
A mature cell is taken from the personfor whom stem cells are to be made; agene for a protein found in embryonicstem cells is inserted.
An egg cell isharvested froma volunteer.
The mature cellbegins to make the
protein, which staysin the cells nucleus.
BRYANC
H
RISTIED
ESIG
N
The nucleus ofthe mature cell isinserted into thestripped-down egg.
OTHER PLAYERSNuclear Reprogramming
Resee Pojet
George Daley Studyng nnogsHarvard Medical School bty to eo-
g nue
Kevin Eggan ReogngHarvard University dut es usng
ste es
Rudolf Jaenisch Cetng toedMIT ste es usng
teed nuetnsfe (CDX2)
The nucleusof the egg isremoved.
The egg reprograms theDNA, but the extra pro-tein modifies the processso that it results in stemcellsbut no embryo.