
English: 
I would like to reiterate something that Jean
said and that is that this colloquy owes its
life to Dr. Tomatis, but the inspiration for
it came from Rich DeVos himself who thought
that the ethics of medicine were just as important
as all of the technological advances that
we’re making. Especially tonight those come
in brilliant contrast with genome editing.
When I was in medical school I didn’t even
know the term existed. Genome editing was
fanciful fiction, so it’s very special.
We’re privileged to have two really good
speakers. The person that was intended to
be the moderator for today was Dr. MacKeigan.
Dr. MacKeigan initially joined the faculty
at the Van Andel Institute and then recently,
I think it was in 2017, that he moved over
to Michigan State University and works in

English: 
TEST, TEST, TEST, TEST, TEST,
TEST,
... .... .... .
... .... .... .... .
>> ON BEHALF OF GRAND VALLEY, I
AM PLEASED TO WELCOME TO THE
ETHICS OF OF GENOME EDITING.
WE ARE PLEASED YOU ARE HERE
TODAY, AND LOOK FORWARD TO
EXCITING SPEAKER, AND DISCUSSION
AND QUESTION AND ANSWER PERIOD.
>>> TONIGHT, WE ARE LIVE
STREAMING THIS COLLOQUY, SO THAT
COMMUNITY MEMBERS, COLLEGE
CLASSES AND PEOPLE HAVE AN
OPPORTUNITY TO PARTICIPATE AT A
DISTANCE.
SO, WHAT THAT MEANS, EVERYONE
WILL BE TALKING INTO A
MICROPHONE AND WILL BE BRINGING
AT THE Q&A, YOU WILL HAVE
MICROPHONES TO TALK INTO SO
EVERYONE CAN HEAR.
>>  WE HAVE A CHANGE IN OUR
AGENDA TONIGHT, WE WERE GOING TO
HAVE ALTA CHARO, BUT SHE IS.
[INDISCERNIBLE]
TO -- UNABLE TO COME, SHE IS
VERY SICK.
BUT DR. MATTHEW PORTEUS, HAS
GRACIOUSLY AGREED TO PRESENT HIS
SECTION AND HERS.
WE WILL HAVE BOTH DR. PORTEUS
AND JEFF MACKEIGAN, ANSWERING
QUESTIONS FOR US.
SO, THANK YOU BOTH.
WE REALLY APPRECIATE.
>>> WE ALSO WANT TO THANK ALTA
CHARO, SHE DID SEND HER SLIDES,
AND SHE WAS COMMUNICATING QUITE
A BIT, WITH DR. PORTEUS, AND WE
WOULD LIKE TO THANK HER FOR
CONTRIBUTING.
>>> I WOULD LIKE TO THANK THE
DEVOS FOUNDATION, FOR SUPPORTING
ALL OF US, AND DR.
>>> FOR THOSE
ON OUR COLLOQUY
COMMITTEE, IF YOU ARE ON A
COMMITTEE, PLEASE STAND AND BE
RECOGNIZED.
[APPLAUSE]
>> I ALSO WANT TO RECOGNIZE,
DIANE, SHE IS IN THE BACK, IF
YOU CAN WAVE, DIANE.
SHE DOES A LOT OF COORDINATING
FOR THIS EVENT.
I WANT TO THANK BLUE CROSS AND
BLUE SHIELD OF MICHIGAN, THEY
PROVIDED THE RECEPTION.
SO WE REALLY APPRECIATE THAT.
>>> THE FINAL THING I WANT TO
TALK ABOUT, IS DR. FARR, WE GOT
HIM, AND HE HELPS US COORDINATE,
LOOK UP SPEAKERS, AND HE DOES A
LOT OF WORK, JUST DISCUSSING THE
CONTENT OF WHAT WE SHOULD
DESCRIBE WITH THE SPEAKERS.
SO DR. FARR, WOULD YOU PLEASE
COME UP?
[APPLAUSE]
>> THIS IS THE 27th COLLOQUY
WE HAVE PRESENTED.
AND DR. PORTEUS SAID TO ME,
NEVER BEFORE HAS A SPEAKER EVER
FAILED TO SHOW UP.
IT'S ALL YOUR FAULT.
I AM PARAPHRASING, BUT HE
IMPLIED THAT.
>>> JUST A FEW HOUSEKEEPING
THINGS, REMEMBER THAT SILENT
PHONE MODE.
REMEMBER TO SIGN UP FOR CME
CREDIT IN THE BACK.
THERE ARE SOME QUESTION CARDS, I
THINK, THAT WILL BE AVAILABLE,
AND IF YOU HAVE A QUESTION
DURING THE AUDIBLE PART OF THE
QUESTION AND ANSWER, BE SURE TO
USE A MICROPHONE SO THAT PEOPLE
THAT WE ARE LIVE STREAMING THIS
TO, CAN LOOK IT UP.
>>> IF YOU HAVE HEARING AIDS,
THEY ARE COMPATIBLE WITH THE T. 
LOOP IN THIS AUDITORIUM.
I THINK THAT'S ALL THE
HOUSEKEEPING THINGS I HAVE GOT.
>>> I WOULD LIKE TO REITERATE
SOMETHING JEAN SAID, THIS
COLLOQUY OWES ITS LIFE TO DR.
DR. TOE MAT STAY WITH
US.
>>> WE ARE PRIVILEGED TO HAVE
TWO REALLY GOOD SPEAKERS.
THE PERSON THAT WAS INTENDED TO
BE THE MODERATOR FOR TODAY, WAS

English: 
DR. MACKEIGAN.
HE INITIALLY JOINED THE FACULTY
AT THE VAN LISTEN INSTITUTE.
RECENTLY, I THINK 2017, HE MOVED
OVER TO MICHIGAN STATE
UNIVERSITY AND WORKS IN THE
LABORATORY JUST DOWN THE HILL
FROM WHERE HE USED TO WORK.
HE DOES GENE EDITING AS PART OF
HIS DAILY ACTIVITY.
I SHOULD MENTION BEFORE I
FORGET, HE GOT HIS BACHELOR'S
DEGREE FROM THE UNIVERSITY OF
COLORADO, AND WENT ON TO NORTH
CAROLINA, FOR HIS PHD.
POST DOCTOR LITERALLY, HE WAS
AT
HARVARD, AND TEMPORARILY JOINED
THE STAFF AT
NAVARTUS.
HE HAS HAD QUITE A BIT OF
EXPERIENCE, AND WE ARE THANKFUL
HE COULD COME.
WITHOUT FURTHER ADO, DR. JEFF
MACKEIGAN.

English: 
the laboratory just down the hill from where
he used to work. He does gene editing as part
of his daily activity. I should mention, before
I forget, that he got his Bachelor’s Degree
from the University of Colorado and then went
to North Carolina for his PhD. Post-doctorally
he was at Harvard Medical School and then
temporarily joined the staff at Novartis.
It’s a big pharma, I think. He’s had quite
a bit of experiences and I think we’re very
lucky to have someone with his experience
now that Alta Charo can’t come. So without
further ado, Dr. Dr. MacKeigan.
Dr. MacKeigan:
It is such a privilege to be introduced by
Dr. Farr. It feels like family. He knew my

English: 
father quite well and it’s just a privilege
to have you introduce me. My job today, before
we get to the more panel session, is really
to introduce a leader in the field, what we
call a “rockstar” in the world of genome
editing and providing high-quality care to
pediatric patients. Dr. Matthew Porteus is
an Associate Professor at Stanford University.
He received both his combined MD and PhD degrees
from Stanford where he focused on mammalian
forebrain development. He then did his residency
and clinical training at Boston Children’s
Hospital and his postdoctoral fellowship just
down around the corner under the guidance
of David Baltimore. Dr. Porteus is considered
a pioneer in the field of genome editing with
numerous publications found in many high-impact
journals such as Nature and the New England

English: 
>>  IT IS SUCH A PRIVILEGE TO BE
INTRODUCED BY DR. FARR.
FEELS LIKE FAMILY.
HE KNEW MY FATHER QUITE WELL,
AND IT IS A PRIVILEGE TO HAVE
YOU INTRODUCE ME.
>>> MY JOB TODAY, BEFORE WE GET
TO THE MORE PANEL SESSION BEINGS
IS TO INTRODUCE A LEADER IN THE
FIELD, WHAT WE CALL A ROCK STAR
IN THE REALM OF GENOME EDITING.
DR. MATTHEW PORTEUS, IS A
PROFESSOR AT STANFORD
UNIVERSITY.
HE RECEIVED BOTH HIS COMBINED
FREE FROM STANFORD, WHERE HE
FOCUSED ON BRAIN DEVELOPMENT.
>>> HE DID HIS POST -- SORRY,
HIS TRAINING AT BOSTON HOSPITAL,
AND AROUND THE CORNER AT DAVID
BALTIMORE.
>>> DR. PORTEUS IS CONSIDERED A

English: 
Journal of Medicine. He has received numerous
awards and grants from the National Institute
of Health, the Burroughs Welcome Fund, and
the Howard Hughes Medical Institute. He most
recently received a large award from the California
Institute of Regenerative Medicine for his
research on CRISPR technology and for applying
that to correct a mutation in sickle cell
disease. So, let’s get started and welcome
Dr. Porteus.
Dr. Porteus:
Thank you, Dr. Farr, Luis, and Jeff for that
really kind introduction, and thank you all
for coming and spending the next half hour
listening to me talk as Matt Porteus and then
the next 20 or 25 minutes talking to you as
Alta Charo. Alta is a JD and I have a lot
of letters after my name but JD are not two

English: 
PIONEER IS IN THE FIELD OF
GENOME EDITING, WITH NUMEROUS,
SUCH AS NATURE AND THE NEW
ENGLAND MEDICINE.
HE HAS RECEIVED NUMEROUS AWARDS
AND GRANTS.
FROM THE NATIONAL INSTITUTE OF
HEALTH.
HOWARD HUGHES MEDICAL INSTITUTE.
>>> HE MOST RECENTLY RECEIVED A
LARGE AWARD FOR REGENERAL ACTIVE
MEDICINE ON RESEARCH FOR CRISPER
TECHNOLOGY AND SICKLE-CELL
DISEASE.
SO, LET'S GET STARTED AND
WELCOME DR. PORTEUS.
[APPLAUSE]
>>  ALL RIGHT, WELL THANK YOU,
TO DR. FARR, AND I CAN'T SAY
YOUR LAST NAME YET -- AND JOSEPH
FOR THAT KIND INTRODUCTION.
THANK YOU FOR COMING FOR

English: 
LISTENING TO ME TALK, AND NEXT
WILL BE ALWAYS AT A CHARO.
ALTA IS A JD.
I HAVE A LOT OF LETTERS BEHIND
MY NAME, BUT JD IS NOT ONE OF
THEM.
SO I WILL DO THE IMPOSSIBLE
TRYING TO IMPERSONATE.
>>> WHAT WE WILL TALK ABOUT
SCIENCE OF GENTLEMAN MODEM
EDITING WITH THE CASPER TOOL,
AND SOME ETHICS OF IT.
>>> AS PROFESSOR CHARO WILL GO
MORE INTO THE REGULATORY AND
ETHICS OF GEE GNOME EDITING.
IT IS CHANGING THE NUCLEUS IN
THE CELL, WITH PRECISION.
WE CAN NOW ALTER THE SEQUENCE OF
OF DNA LIKE WE CAN ALTER A WORD
DOCUMENT.
>>> IT IS A LITTLE MORE
DIFFICULT.

English: 
of them so I’ll try to do my best impersonation
of somebody who is impossible to impersonate.
What I’m going to talk a lot about in this
first talk is sort of the science and technology
of genome editing using the CRISPR/Cas9 tool
and then end with a little discussion on some
ethics of it and then, as Professor Charo
will go a lot more into the regulatory and
ethics of genome editing.
What is genome editing? Genome editing is
this new way of changing the sequence of the
DNA within a cell with single nucleotide or
single-letter precision so that we can now
alter the sequence of DNA, as I said, just
like we can alter a Word document on our computer.
But it’s a little bit more difficult and
the way it works is that we design a protein,
and there are various different types of protein
we can design, but all of them work in the
same way which is they are designed to recognize

English: 
WE DESIGN A PROTEIN, AND THERE
ARE VARIOUS TYPES OF PROTEINS WE
CAN DESIGN.
ALL OF THEM WORK IN THE SAME
WAY.
THEY DESIGN A SEQUENCE IN THE
GEE GNOME, WHEN THEY BIND INTO
THE SEQUENCE, THEY WILL MAKE A
DOUBLE STRANDED BREAK.
>>> AT THAT POINT, THE CELL
WANTS TO REPAIR THAT BREAK, AND
PUT THE TWO ENDS OF THE DNA BACK
TOGETHER.
IT CAN DO IT IN ONE OF TWO WAYS.
ONE WAY GOING DOWN THE
RIGHT-HAND SIDE, IS A PROCESS WE
CALL JOINING, WHERE THEY ARE
STITCHED BACK TOGETHER.
THIS IS GENERALLY AN ACCURATE
PROCESS.
>>> IF IT IS COMPLETELY
ACCURATE, IS RECONSTITUTES, THAT
THE NUCLEI IS BOUND TO, SO IT
CUTS IT.
EVENTUALLY YOU CAN CREATE LITTLE
NIBBLES AT THE SIDE OF THE
BREAK.
THIS ALLOWS YOU TO CREATE MEW
TUGSTATIONS.
THIS IS A GOOD WAY OF BREAKING
THINGS.
>>> THE OTHER WAY THE CELERY

English: 
a specific sequence in the genome and when
they bind to that sequence they’ll cut the
DNA into two parts. They’ll make what we
call a double-stranded break. At that point
the cell wants to repair that break, wants
to put the two ends of the DNA back together.
It can do it in one of two ways: One way,
going down the righthand side, is a process
we call non-homologous end-joining in which
the two ends are simply stitched back together.
This is generally an accurate process. If
it’s completely accurate, of course it reconstitutes
the sequence that the nuclease bound to and
so it re-cuts it again. If you get cutting
and repair, eventually you can create little
nibbles at the site of the break, what we
call insertions and deletions, and this allows
you to create mutations at specific sites
in the genome. This is a good way of breaking
things. The other way that the cell repairs
double-stranded breaks is by homologous recombination.
We can harness this homologous recombination

English: 
PAIRS DOUBLE STRANDED BREAKS, IS
BY HUE MOLE GUS, BY NOT ONLY
CREATED A DOUBLE STRANDED BREAK,
BUT AN EXTRA SEQUENCE OF DNA.
THE
THE HOMOLOGOUS, IS A COPY/--
PASTE IT OVER THE BREAK.
BY DESIGNING THE DONOR DNA, WE
CAN INTRODUCE SPECIFIC CHANGES
ACTION SINGLE LETTER CHANGES,
AND RECESSIVE GENES PRECISELY
INTO THE
GENOME EDITING.
ONE CAN THING OF IT AS A FIND
AND REPLACE.
>>> YOU ASK THE MACHINERY, TO

English: 
pathway by not only creating a specific double-stranded
break, but also by providing an extra sequence
of DNA, what we call a donor DNA. The homologous
recombination machinery of the cell will use
this donor DNA through what you can think
of as a copy and paste mechanism and make
a good copy of the undamaged donor DNA and
paste it over the break. By designing the
donor DNA to have sequence changes, we can
introduce specific sequence changes, single-letter
changes or actually introduce large cassettes
of genes precisely into the genome. This is
what we mean by genome editing.
Again, going to our laptop computers, one
can think of genome editing conceptually as
a find and replace. So, you ask the genome
editing machinery to find a disease-causing
sequence and then you engineer it to replace
it with a non-disease causing sequence.
There are a number of different ways we can

English: 
make that double-stranded break and those
are shown on the right hand side here: Meganucleases,
zinc-finger nucleases, TAL effector nucleases,
and the latest tool called the CRISPR/Cas9
nucleases. As I mentioned, you can add, delete,
or inactivate genes. You can, as I said, it
works by using own cellular repair mechanisms,
but what has really transformed this field
in the last 5 years is the discovery of this
CRISPR/Cas9 platform and that’s because
it has really democratized the ability of
research labs to do genome editing. The reason
for this is that instead of having to design
a protein that recognizes a sequence of DNA,
which is very difficult to do because we don’t
understand the rules, instead we use a small
RNA that we can design to recognize DNA based
on Watson-Crick base pairing and that brings
the nuclease to the site of the break. It’s
much easier to make a CRISPR/Cas9 nuclease.

English: 
FIND A DISEASE-CAUSING SEQUENCE,
AND YOU ENGINEER IT TO REPLACE
IT WITH A NON-DISEASE-CAUSING
SEQUENCE.
>>> SO, THERE ARE A NUMBER OF
DIFFERENT WAYS WE CAN MAKE THAT
BREAK, AND THOSE ARE SHOWN ON
THE RIGHT-HAND SIDE.
USING THIS AS I MENTIONED, YOU
CAN ADD, DELETE OR INACTIVATE
GENES.
YOU CAN, AS I SAID, BY USING THE
OWN CELLULAR REPAIR MECHANISMS.
WHAT HAS TRANSFORMED THIS FIELD,
IS THE DISCOVERY OF OF THE
CRISPER PLATFORM.
THAT'S WHY IT HAS DAMMITSED SO
DO GENOME EDITING.
INSTEAD OF HAVING TO DESIGN A
PROTEIN WHICH IS A SEQUENCE OF
DNA, WHICH IS DIFFICULT TO DO,
BECAUSE WE DON'T UNDERSTAND THE

English: 
It turns out that this system is highly efficient
in a wide variety of cell types including
somatic stem cells and zygotes and we’ll
get into that. It’s actually highly specific.
It’s not perfectly specific, but it’s
very specific. There’s been an explosion
in the use of this tool for basic research
applications.
I am a pediatric hematologist/oncologist,
and I got into this field because I was interested
in developing better therapies for sickle
cell disease. Sickle cell disease is one of
what we estimate is at least 10,000 diseases,
so called monogenic diseases, which are caused
by a single variance in single genes leading
to specific diseases. Most of these diseases
are quite rare, maybe only affecting a few
hundred people around the world, but in some
these diseases affect a large number of people
both in the United States and worldwide. It’s

English: 
RULES, WE USE A SMALL RNA, BASED
OR WATSON PAIRING, AND THAT
BRINGS THE NUKE LAZE TO THE
BREAK.
IT TURNS OUT THIS IS HIGHLY
EFFICIENT IN A WIDE VARIETY OF
CELL TYPES.
WE WILL GET INTO THAT.
IT IS ACTUALLY HIGHLY SPECIFIC.
IT IS NOT PERFECTLY SPECIFIC,
BUT VERY SPECIFIC.
>>> SO, THERE IS AN EXPLOSION IN
THE USE OF THIS TOOL FOR BASIC
RESEARCH APPLICATIONS.
NOW, ONE -- I AM A FEED I CAN'T
TELL TO BEING ON COLORADO GIST,
AND I GOT INTO THIS FIELD TO
DEVELOP BETTER TREATMENT FOR
SICKLE-CELL DISEASE.
MONDAY NO AGAIN MAGIC, IS A
SINGLE GENE TO SPECIFIC
DISEASES.
MOST OF QUITE RARE, MAYBE

English: 
AFFECTING SOME, MAYBE A HUNDRED
AROUND THE WORLD.
IT IS ESTIMATED THAT PERHAPS AS
MANY AS 30 MILLION IN THE U.S.
HAS SOME SORT OF MONDAY GENETIC
DISEASE.
FROM IMMUNE, TO HEART, TO THE
LUNG, TO THE BRAIN.
>>> ANOTHER POINT I WANT TO
MAKE, MANY OF THE DISEASES ARE
RARE, BUT IMPACT A MUCH LARGER
COMMUNITY OF PEOPLE.
NOT ONLY IMMEDIATE FAMILY, BUT
THE SCHOOLS, AND THEIR FRIENDS
AND EXTENDED FAMILY.
>>> SO, A SINGLE PATIENT, IT'S
NOT JUST ONE PATIENT.
YOU ARE ACTUALLY EFFECTING A
LARGE COMMUNITY OF PEOPLE.
>>> SO, WE WOULD LIKE TO DO
THEN, IS APPLY THIS PRECISION TO
MAKING CHANGES IN THE DNA AS A
WAY OF CORRECTING THESE GENETIC
DISEASES RIGHT AT THEIR

English: 
estimated that perhaps as many as 30 million
people in the US have some sort of monogenic
disease. They affect all aspects of medicine
from hematology to the lungs to the immune
system to the heart to the skin to the brain
and many of those diseases are listed. The
other point I want to make is that while many
of these diseases are rare, they impact on
a much larger community of people - not only
their immediate family but the schools and
their friends and their extended family. It’s
not just one patient. You’re actually affecting
a large community of people, so the echoes
of this disease. What we like to do then with
genome editing is apply this precision to
making changes in the DNA as a way of correcting
these genetic diseases right at their foundation.
We can think about doing genome editing in

English: 
FOUNDATION.
>>> WE CAN THINK OF DOING GINO
MEDICINE TINGE, IN ONE OF TWO
WAYS.
WHAT THIS WOULD INVOLVE --
SORRY.
SO, BOTH OF THESE ARE SEMI MATIC
GENOME EDITING, LET ME TAKE
THOSE IN ORDER.
SEMANTIC CELLS MAKE US UP, BUT
WHEN WE DIE, THE CELLS DIE.
THEY DO NOT PASS ALONG THEIR
INFORMATION TO FUTURE
GENERATIONS.
WE CAN EITHER MODIFY THEM BY
BRINGING THEM OUTSIDE THE BODY,
AND MODIFYING THEM BY USE
WILLING THE
--
NOW, THE OTHER
PROCESS TO DO SOMATIC CELL

English: 
one of two ways. One way is what we call ex
vivo genome editing. Both of these are somatic
cell genome editing. Let me take those terms
in order. Somatic cells are cells that live
within us, or make us all up, but when we
die the cells die. They do not pass along
their genetic information to future generations.
We can either modify somatic cells by bringing
them outside the body, in an ex vivo setting,
modify them using the genome editing machinery
which I’ll talk about, and then giving them
back. One can imagine using this to correct
genetic diseases of the blood like sickle
cell disease or developing better cancer immunotherapies
or a whole host of other diseases. The other
approach to doing somatic cell editing is
to do in vivo editing which would mean delivering
the genome editing machinery into the body.
So that would allow us to say edit liver cells
for hemophilia or diseases of the liver or

English: 
the muscle cells for muscular dystrophy or
maybe even brain cells, neurons, for Huntington’s
disease.
If we contrast ex vivo versus in vivo editing
there are pros and cons to both. As I mentioned,
ex vivo editing involves being able to isolate
the patient’s cells, modifying them outside
the body, and then having a way of giving
them back to the patient so that they’ll
take and last for the lifetime of the patient.
What are the advantages? Since we have the
cells outside the body it’s easier to control
the delivery of the genome editing machinery
to those cells. It’s easier to measure what
we’ve done both where we want and where
we don’t want to have things happen. The
disadvantage is we have to know how to isolate
these cells and we have to know how to give
them back. For many of the diseases that I’ve
mentioned, we don’t know how to do that.
For diseases of the blood and immune system,
we do.
What about in vivo editing? As I said it’s
delivering the genome editing machinery to
the patient to genetically modify the cells
where they sit in the liver or the organ that

English: 
GENTLEMAN MODEM EDITING, AND
THAT IS X VIDEO VOW.
FERRIHEME FEEL I CAN'T, OR
DISEASES OF THE LIVER.
MAYBE BRAIN CELLS OR NEURONS FOR
HUNTINGTON'S DISEASE.
>>> THERE ARE PROS AND CONS TO
BOTH.
EXAMINE VIDEO VOW, BEING ABLE TO
TO -- HAVE A WAY TO GIVE THEM
BACK TO THE PATIENT SO THEY WILL
LAST A LIFETIME OF THE PATIENT.
>>> WHAT ARE THE ADVANTAGES?
WELL, SINCE WE HAVE THE CELLS
OUTSIDE OF THE BODY, IT IS
EASIER TO MEASURE, BOTH WHERE WE
WANT, AND DON'T WANT TO HAVE
THINGS HAPPEN.
>>> THE DISADVANTAGE WE HAVE TO
KNOW HOW TO ISOLATE THESE CELLS,
AND GIVE THEM BACK.
FOR MANY OF THE DISEASES, I'VE
MENTIONED, WE DON'T KNOW HOW TO
DO THAT.

English: 
they normally belong in. This gives us a potential
method to edit cells for which we do not know
how to isolate and expand and transplant,
cells of the eye or the brain or the liver
or the somatic muscle or the heart. And it
doesn’t involve any cell manufacturing outside
the body. What are the cons of this approach?
Because we’re delivering the drug, the genome
editing drug into the body, we don’t control
the on-target and off-target effects as well
as we would if we were modifying the cells
outside the body. There are significant challenges
to delivering the genome-editing machinery
to the right tissues. How do we get our machinery
to the liver and not to other tissues? Finally,
I’m going to mention a little bit that there
are problems that the genome editing systems
we use are foreign proteins and we have the
problem, the barrier of the human immune response.
So, I’m going to focus in the next few slides
on what we’ve been doing in terms of applying
genome editing to sickle cell disease. Sickle

English: 
FOR THE DISEASE Z OF THE BLOOD
AND IMMUNE SYSTEM, WE DON'T.
>>>
EXAMINE RECEIVE VOW, AND
THIS GIVES US POTENTIAL METHOD
TO ISOLATE CELLS THAT WE DON'T
KNOW HOW TO TRANSPLANT.
EYE, LIVER, OR HEART.
IT DOESN'T INVOLVE CELL
MANUFACTURING OUTSIDE OF THE
BODY.
>>> WHAT IS THE APPROACH?
BECAUSE WE ARE DELIVERING THE
--
THERE ARE SIGNIFICANT CHALLENGES
TO DELIVERING IT TO THE RIGHT
TISSUES.
HOW DO WE GET OUR MACHINERY TO
THE LIVER AND NOT OTHER TISSUES.
>>> FINALLY, I WILL MENTION THAT
THERE ARE PROBLEMS THAT THE GINO

English: 
cell disease is an autosomal recessive disease
caused by a single nucleotide change, a change
in the beta globin gene, an A to a T, which
leads to a single amino acid change in the
protein from a charged glutamic acid to a
polar veiling. When you have a hemoglobin
molecule that’s normally a tetramer in red
blood cells with the sickle cell change, it
polymerizes and it converts a round, red blood
cell into a stiff, red sickle shape red blood
cell giving the disease its name. These stiff
sickle red blood cells can cause occlusions
in the blood vessels and prevent oxygen from
getting delivered to the distal tissues. If
you have this disease in Africa, the median
lifespan is on the order of 5 to 8 years of
age. If you have this disease in the United
States, the median lifespan is in the mid
40’s. It shows that we can modify this disease
by having a reasonably good healthcare system,

English: 
EDITING THAT WE USE.
>>> I WILL FOCUS ON THE NEXT FEW
SLIDES WHAT WE ARE DOING
APPLYING GENTLEMAN MODEM
EDITING.
IT IS A RECESSIVE DISEASE,
CAUSED IN THE BETA GLOBE, THAT
LEADS TO A SINGLE AMINO ACID, TO
A POLAR VEY LEAN.
WITH THE SICKLE-CELL CHANGE, IS
CONVERTS A ROUND RED BLOOD CELL
INTO A STIFF CYCLE SHAPE RED
BLOOD CELL GIVING THE DISEASE
ITS NAME.
>>> THE RED BLOOD CELLS CAN
CAUSE OWE INCLUSIONS IN THE
VESSELS, AND BLOOD BEING
DELIVERED FROM THE TISSUES.
>>> IF YOU HAVE THIS DISEASE IN
AFRICA, THE LIFE SPAN IS 5-10

English: 
but we still don’t achieve what we want.
Fundamentally then we want to change hemoglobin
S that GTG to hemoglobin A, a GAG.
The disease only affects red blood cells and
so normal red blood cells live for about 100
days. We don’t want to modify red blood
cells because we would only get a transient
benefit from that. Instead of trying to modify
or correct red blood cells, we have to correct
hematopoietic stem cells. Hematopoietic stem
cells are somatic stem cells that generate
all of the blood in the body for the lifetime
that we live. If we can correct the hematopoietic
stem cell, we can then get red blood cells
that don’t have sickle cell disease for
the rest of their life.
One way of giving somebody corrected hematopoietic
stem cells is by doing what we call an allogeneic
hematopoietic stem cell transplant, or a bone
marrow transplant. In this procedure we take

English: 
YEARS OF AGE.
AND IF YOU HAVE IT IN THE U.S.,
UP TO 30 YEARS.
>>> WE WANT TO CHANGE
GAG TO GUG
GUG.
>>> >>> NORM MOLE RED BLOOD
CELLS LIVE FOR ABOUT A HUNDRED
DAYS.
WE DON'T WANT TO MODIFY RED
BLOOD CELLS, BECAUSE WE WOULD
ONLY GET
A -- HER MATIC STEM
CELLS GENERATE ALL THE BLOOD IN
THE BODY FOR THE LIFETIME WE
LIVE.
IF WE CAN CORRECT THAT, WE GET
RED BLOOD CELLS THAT DON'T HAVE
SICKLE-CELLS FOR THE REST OF
THEIR LIFE.

English: 
bone marrow stem cells from somebody who doesn’t
have sickle cell disease and we give them
to somebody who does have sickle cell disease
and we create space for those stem cells by
giving the patient high doses of chemotherapy
to allow our stem cells to take.
It turns out that if you have an appropriate
donor this works quite well. There is about
a 95% cure rate by doing an allogeneic stem
cell transplant for sickle cell disease and
this was a paper published in 2016. The problem
is that with this allogeneic stem cell transplant,
only about 10 to 15% of patients actually
have a donor. There is still a 5% mortality
from the process and there are problems, because
it’s an immunologic mismatch, you have problems
of poor immune function and graft-versus-host
disease that limit the places and number of
patients who actually can receive this therapy.
What we’ve been working on then is replacing
allogeneic cells with the idea of correcting
the patient’s own cells.

English: 
ONE WAY OF CORRECTING IT, IS
DOING WHAT WE DO BY A BONE MARIO
TRANSPLANT.
IN THIS PROCEDURE, WE TAKE BONE
MARIO STEM CELLS FROM SOMEBODY
WHO DOESN'T HAVE SICKLE-CELL
DISEASE, AND GIVE THEM TO
SOMEBODY WHO DOES HAVE
SICKLE-CELL.
AND THEN HIGH DOSES OF
CHEMOTHERAPY, AND IT TURNS OUT,
IF YOU WERE AN APPROPRIATE DONE
ANOTHER, THIS WORKS QUITE WELL.
THERE IS A 95% CURATE FOR
SICKLE-CELL DISEASE.
THIS WAS A PAPER PUBLISHED IN
2016.
THE PROBLEM WITH THE TRANSPLANT,
ONLY TEN TO 12 PATIENTS ACTUALLY
HAVE A DONOR.
STILL 5% MORTAL AT THIS FROM THE
PROCESS.
THERE ARE PROBLEM BECAUSE --
PROBLEMS WITH AUTOIMMUNE HAVE

English: 
IT.
SO YOU LIMIT THE AMOUNT OF
PEOPLE WHO CAN RECEIVE THE
THERAPY.
>>> WE HAVE BEEN USING THE
CRISPER CAST 9 TOOL TO DO THAT.
AND WE USE IT IN THE FOLLOWING
FORM:  RYAN BOUGH NUCLEAR
COMPLEXION.
IT HAS MULTIPLE FUNCTIONS, BUT
THE MOST IMPORTANT FUNCTION OF
WHICH, IT CAN MAKE THE BREAK IN
THE DNA.
IN ORDER TO KNOW WHERE TO MAKE
THE BREAK, IT IS GUIDED, BY THE
GUIDE, SHOWN IN THE BUBBLES.
>>> SO THE SEQUENCE SHOWN WITH
THE BUNCH OF LINES, TELLS WHERE
THE COMPLEX SHOULD GO AND MAKE
THE BREAK.
WE DELIVER IN THIS COMPLEX, AND
MAKE THIS PROTEIN COMPLEX IN A
TEST TUBE IN A LAB, AND MIX IT
WITH OUR CELLS, AND WE

English: 
We have been using the CRISPR/Cas9 tool to
do that. We use the CRISPR/Cas9 tool in the
following form which is what we call a ribonucleoprotein
complex. We take the Cas9 protein which is
depicted here in this grey blob which has
multiple functions but the most important
function of which is that it can make that
break in the DNA. In order to know where to
make that break, it is guided by what we call
the guide RNA which is shown there in the
little bubbles. The 20 nucleotide sequence
that’s shown with a bunch of lines there,
tells where this complex should go and make
the break. We deliver this complex. We make
this protein RNA complex in a test tube in
the lab and then we mix it with our cells
and we zap, we electrocute the cells basically
to make holes, and this complex gets in. That
makes the break. Now we need to deliver that
piece of DNA that’s going to fix the break

English: 
ELECTROCUTE THE CELLS TO MAKE
HOLES, AND THIS COMPLEX GETS IT
IN.
>>> NOW WE NEED TO DELIVER THAT
PIECE OF DAP AND FIX THE BREAK
OR MUTATION.
FOR THAT, WE USE A VIRUS.
THE REASON WE USE THE VIRUS,
BECAUSE THEY HAVE EVOLVED TO GET
INTO CELLS.
WE KNOW IF YOU DELIVER INTO
CELLS, CELLS HAVE A GOOD WAY OF
DETECTING THAT
WAY TO GET IN.
>>> WE FOLLOW THAT, BY
DELIVERING THE VIRUS TO GIVE
THAT CORRECTION, THE DONOR DNA.
>>> IN SUMMARISING ABOUT FOUR
YEARS OF WORK, AND ABOUT FIVE
PEOPLE'S FOUR YEARS OF WORK IS
IN THIS ONE SLIDE.
WHAT WE ARE ABLE TO DO NOW, IF
WE TAKE STEM CELLS, FROM

English: 
and fix that mutation.
For that we actually use a virus. The reason
we use a virus is that viruses have evolved
to get into cells without them being detected.
What we know is that if you deliver DNA into
cells, cells have a really good way of detecting
that as a foreign invasion so we harness the
ability of viruses to get into cells. So in
our process then, we deliver our nucleases,
this RNP complex, and then we follow that
by delivering the virus to give that correction,
that donor DNA.
In summarizing about 4 years’ of work and
about 5 peoples’ 4 years’ of work is in
this one slide. What we’re able to do now
is if we take stem cells from patients with
sickle cell disease, they’re marked by a
protein called CD34, and we measure how many
genes we corrected in those patients’ cells,
we find that we can now on average correct

English: 
about 70% of the alleles in patients’ hematopoietic
stem and progenitor cells. You might be asking
yourself is 70% enough? And it turns out it
probably is enough. We have some debates about
whether 2% would be enough or 5% would be
enough or 20% would be enough, but everyone
agrees that 20% correction would probably
be sufficient to cure this disease.
This is now what we’re thinking about doing
next year in a clinical trial. We would isolate
hematopoietic stem and progenitor cells from
a patient. I show a baby here because ultimately
we’re going to want to treat people young
before the damage from the disease imparts
itself but the FDA will require us to treat
older patients because of issues with consent
and assent. Nonetheless, we will harvest stem
cells from our patient. We’ll bring them
into a laboratory where we will modify them
under careful GMP condition, good manufacturing

English: 
PATIENTS WITH SICKLE-CELL, AND
WE MEASURE HOW MANY GENES DID WE
CORRECT IN THE PATIENT'S CELLS,
WE FIND WE CAN CORRECT ABOUT 70%
INPATIENTS.
>>> YOU MIGHT BE ASKING YOURSELF
IS 70% ENOUGH?
IT TURNS OUT IT PROBABLY IS
ENOUGH.
EVERYONE AGREES THAT 20%
CORRECTION WOULD BE -- WOULD
PROBABLY BE SUFFICIENT TO CURE
THIS DISEASE.
>>> SO, THIS IS NOW WHAT WE ARE
THINKING ABOUT DOING NEXT YEAR
IN A CLINICAL TRIAL.
WE WOULD ISOLATE FROM A PATIENT.
I SHOW A BABY HERE, ULTIMATELY,
WE WANT TO TREAT PEOPLE YOUNG,
BEFORE THE DAMAGE FROM THE
DISEASE I AM PARTS ITSELF, BUT
THE FDA WILL REQUIRE US TO TREAT

English: 
OLDER PATIENTS BECAUSE OF
CONSENT.
>>> WE WILL BRING THEM INTO A
LABORATORY, MODIFY THEM UNDER
WHAT WE CALL GMP CONDITIONS,
WHERE EVERYTHING IS CONTROLLED.
WE KNOW, BASICALLY, THE SUPPLY
CHAIN OF EVERYTHING.
THOSE CELLS WILL BE
CHARACTERIZED, TO MAKE SURE WHAT
WE WANTED TO DO, AND THE PATIENT
WILL COME BACK TO OUR HOSPITAL,
OUR HOSPITAL FIRST.
BUT THEN, HOPEFULLY HOSPITALS
ALL ACROSS THE WORLD, TO RECEIVE
THE BONE MARIO TRANSPLANT.
IT WILL REQUIRE THE PATIENT TO
GET HIGH DOSES CHEMOTHERAPY, BUT
NOT AS HIGH, BUT TO CREATE SPACE
IN IN THE MARIO, SO OUR MODIFIED
CELLS WILL START MAKING BLOOD.
>>> THIS IS SOMETHING I AM
WORKING NOW, SO THE LABORATORY
TEAM WAS THREE TO FIVE

English: 
practice conditions, where everything is controlled.
We know basically the supply chain of everything.
Those cells will then be characterized to
make sure we’ve done what we wanted to do
and not done something that we didn’t want
to do. And then the patient will come back
to our hospital, our hospital first but then
hopefully hospitals all over the country and
world, to receive those cells as part of an
autologous bone marrow transplant. Autologous
transplant will require the patient to get
high doses of chemotherapy, though not quite
as high if they have to undergo an allogeneic
transplant, to create space in the bone marrow
so that our modified corrected cells can get
in and graft and start making blood. As I
said, this is something that I’m working
now with, so that the laboratory team was
about 3 to 5 scientists. The team now to take
what we’ve done in the lab to the clinic
has now grown to about 30 different people.
It’s a whole different, sort of process.

English: 
Many of you may have heard about the problem,
the CRISPR/Cas9 are great but they have a
lot of off-target effects. I want to tell
you that I don’t think that’s the biggest
problem and I’ll show you why in the next
few slides.
What do we mean by off-target effects? The
concern is that the nuclease, we’ve designed
it to recognize one sequence of DNA, but it
goes to another sequence of DNA and makes
a break there. It might cause a mutation somewhere
we don’t want. We worry are we making a
mutation that might cause something bad? Let
me put this all in context though. First of
all, we have tremendous diversity in this
room and in the world. We’ve done whole
genome sequencing now, I’m citing the study
here that was done from Stanford, it’s estimated
that we all individually contain, so our genome
has 6 billion base pairs. Each of us has 2.4

English: 
SCIENTISTS, BUT THE TEAM TO TAKE
TO THE CLINIC HAS GROWN TO ABOUT
30 DIFFERENT PEOPLE.
IT IS A WHOLE DIFFERENT PROCESS.
>>> MANY MAY HAVE HEARD, THE
PROBLEM, WELL, THESE CRISPER ARE
GREAT, BUT HAVE SIDE EFFECTS.
I WILL SHOW YOU WHY THAT'S NOT A
BIG PROBLEM.
>>> FIRST OF ALL, I WANT TO --
WHAT DO WE MEAN BY OFF TARGET
EFFECTS.
THE CONCERN IS, THE NUKE LAYS,
BUT IT GOES TO ANOTHER SEQUENCE,
AND MAY CAUSE A MUTATION.
WE WORRY, ARE WE MAKING A
MUTATION THAT MAY CAUSE
SOMETHING BAD.
>>> LET ME PUT THIS ALL IN
CONTEXT THOUGH.
WE HAVE TREMENDOUS DIVERSITY IN
THIS ROOM AND THE WORLD.
>>> I CITING THE STUDY FROM
STANFORD, IT IS ESTIMATED THAT

English: 
WE ALL, INDIVIDUALLY CONTAIN,
2 -- SO, OUR GENOME HAS
6 BILLION BASE PLAYERS.
>>> EACH OF US 2.4 MILLION
SINGULAR TYPE VARIANCE.
SO, WE HAVE LOTS OF VARIABILITY,
THIS INCLUDE INSERTIONS AND
DELETIONS.
WE ARE ALL BORN DIFFERENTLY.
FORTUNATELY.
DIVERSE TEE IS GOOD.
>>> AS SOON AS OUR CELLS DIVIDE,
WE CREATE MORE DIVERSE TEE.
EVERY TIME A NEW CELL 2000, AND
MUTATIONS ARE A FACT OF LIFE.
EVENTUALLY, OR SOMETIMES, WELL
50% OF US, DEVELOP MUTATIONS
LEADING TO CANCER, BUT THAT CAN
TAKE DECADES OR YEARS.
THAT'S A BURDEN THAT I LIST
THERE.
>>> EACH DAY WE ARE LIVING, WE
ACQUIRE 10 TRILLION MUTATIONS.
IT IS DISTRIBUTED THROUGHOUT OUR

English: 
million single nucleotide variances. So single
nucleotide changes that’s unique. So we
have lots and lots of variability and these
include insertions and deletions and structural
variance. We’re all born differently, fortunately.
Diversity is good. But as soon as our cells
start dividing we generate even more diversity
because every time a cell divides, it generates
another 10-20 new mutations. So mutations
are sort of a fact of life. About 50% of us
develop mutations that end up leading to cancer,
but that can take decades or years. That’s
sort of the mutational burden that I list
there. Each day that we’re living we acquire
close to 10 trillion new mutations in our
body. They’re distributed through all the
cells in our body. It didn’t take me quite
6 hours to fly here from California, it was
about 4 hours, but just being exposed to the
cosmic radiation by being in an airplane is

English: 
inducing mutations in my cells. Now, about
100-fold less than just living so I think
it was worth it. Getting a body CT scan exposes
people to radiation and that generates new
mutations and so on and so forth. When we,
I’ll show you the data, but when we calculate
how many new mutations might be created by
genome editing on the far right, we think
it’s 3, 4, 5, even 6 logs lower than what’s
occurring in our body just by chance. Again,
context here.
The other thing is that the FDA has approved
a genome editing trial run by a company and
out of City of Hope and they were using zinc
finger nucleases, not CRISPR/Cas9 nucleases,
and they found using their nuclease that was
targeting a gene that’s involved in the
biology of HIV, that they found 4 off-target
sites. Some of these off-target sites were
in the middle of genes and the frequencies
were 1%, 5%, 12%, and 20%. The investigators
and the FDA agreed that they had done a sufficient

English: 
BODY.
>>> IT TOOK ME ABOUT FOUR HOURS
FROM CALIFORNIA, BUT BEING IN AN
AIRPLANE, IS INDUCING MY
CELLS.
>>> GETTING A BODY CT SCAN
EXPOSES PEOPLE TO RADIATION, AND
THAT AGAIN RATES NEW MUTATIONS.
>>> I WILL SHOW YOU THE DATA,
WHEN WE CALCULATE HOW MANY WE
HAVE ON THE FAR RATE, WE THINK
IT IS 6 LOGS LOWER THAN WHAT IS
OCCURRING IN OUR BODY BY CHANCE.
>>> AGAIN, CONTEXT HERE.
>>> THE OTHER THING, THE FDA HAS
APPROVED A GENOME EDITING TRIAL,
AND THEY WERE LOOKING AT NEW
ONES.
>>> THEY WERE TARGETING A GENE
INVOLVED IN THE BIOLOGY, THEY
FOUND OFF TARGET SIGHTS.
SOME WERE OFF GENES, AND

English: 
amount of functional studies to show that
these changes weren’t going to be harmful
so they’ve allowed the trial to proceed
and it has been undergoing now for the last
3 or 4 years and there has been no report
of harm.
Even as we have been developing our CRISPR/Cas9
system, Cas9 itself is being improved so this
was work we did in collaboration with a company
and without going into too many details, they’ve
developed a variant of Cas9 that’s more
specific than the variant we have been using
for the last 3 years. It’s about 10-fold
more specific. We can only find 2 sites where
our Cas9 cuts. With the wild-type version
of Cas9 and now with this variant, this highly-specific
Cas9, the one site, what we call off-target
3, basically goes below the limit of detection
and off-target 1 goes from a frequency of
about 14% to 1% so we’re improving the specificity

English: 
FREQUENCIES, WERE 5%, 20%.
BUT THE INVESTIGATORS AND F -- A
AGREED, THEY HAVE DONE A
FUNCTIONAL AMOUNT OF STUDIES,
THAT THEY WILL NOT BE HARMFUL,
SO THEY ALLOWED THE TRIAL TO
PROCEED, AND IT HAS BEEN FIVE
YEARS, AND NO REPORT OF HARM.
>>> EVEN THOUGH WE HAVE BEEN
DEVELOPING OUR SYSTEM, IT HAS
BEEN IMPROVED.
WITHOUT GOING INTO TOO MANY
DETAILS, THEY HAVE DETAILS OF
CAST 9, THAT IS MORE SPECIFIC
THAN THE VARIANT WE HAVE BEEN
USING.
IT IS MORE SPECIFIC.
WE CAN ONLY FIND TWO SIGHTS
WHERE CAST 9 CUTS.
AND NOW WITH THE VARIANT, HIGH

English: 
FIDELITY, HIGH SPECIFIC CAST 9,
OFF SIGHT, BASICALLY GOES BELOW
THE LEVEL OF DETEXT, AND GOES
FROM 14% TO 1%.
SO, WE ARE IMPROVING THE
SPECIFICITY ALL THE TIME.
>>> SO, INVITE ME BACK IN 2020,
AND I WILL TELL YOU IF OUR
CLINICAL TRIALS ARE
WORKING.
>>> THE CASINO NINE PROTEIN
COMES FROM BACTERIA.
THE COMMON FORM, ARE FROM STREP
THROAT, AND STAFF OROUS IS IN
OUR NOSE ALL THE TIME.
>>> BECAUSE IT IS A PROTEIN,
WHEN YOU GIVE IT TO AN ANIMAL --
THIS IS A STUDY OUT OF BOSTON --
THE ANIMAL DEVELOPED AN IMMUNE

English: 
all the time. That’s good. Invite me back
in 2020 and I’ll tell you if our clinical
trial is actually working or not.
I mentioned that the human immune system may
be a potential barrier to in vivo genome editing.
Why do I say that? The Cas9 protein comes
from bacteria; the most common forms of Cas9
that we use are derived from Strep pyogenes
and Staph aureus. So Strep pyogenes, strep
throat; Staph aureus which is on our skin
or causes abscesses, are in our nose all the
time. Because it’s a foreign protein, when
you give it to an animal... In this case this
is a study that came out of Boston, the animal
developed an immune reaction to it. These
were mice that were given Cas9 as part of
therapy for muscular dystrophy and they cured
the mice of the muscular dystrophy but what

English: 
REACTION TO IT.
THESE ARE MICE THAT WERE GETTING
IT FOR MUSCULAR DISFEE.
BUT THEY DEVELOPED A -- THE MICE
DID FINE.
BUT YOU CAN IMAGINE THAT IF YOU
TRIED TO GIVE THESE MICE CAST 9
AGAIN, THEY ARE VACCINATED, AND
THEY WOULD END UP WITH NO EFFECT
ACTIVENESS AT ALL OR AN IMMUNE
RESPONSE.
>>> WE WONDERED SINCE THE CAST 9
COMES FROM BACTERIA THAT ARE ON
MOST HUMANS, DO THEY HAVE
IMMUNITY FROM CAST 9?
>>> THERE ARE TWO FLAVOURS OF
CAST 9, ONE FROM STAFF
POWERROUS, BUT THAT 70% OF
US
HAVE ANTIBODIES, AND IT ALREADY

English: 
they found was that the mice developed T cells
and an immune response to the Cas9 protein.
The mice did fine but you can imagine that
if you tried to give these mice Cas9 again,
they’re basically vaccinated and you would
end up with either no effectiveness at all
or an overwhelming immune response.
We wondered that since the Cas9 comes from
bacteria that are on most humans, do we have
preexisting immunity to Cas9? What we found
is that about 70% of us have, and there are
two sort of flavors of Cas9 we use, one is
from Staph aureus, one from Strep pyogenes,
that about 70% of us have antibodies that
recognize these forms of Cas9 showing that
in fact our immune system already recognizes
the genome editing tool that we’ve been
working on. This means that it’s going to
be challenging to give this form of Cas9 to
patients.

English: 
What are the implications of this? One is
that I think if we tried to give Cas9 to humans
to modify cells in vivo, inside the body,
that we could cause a potentially harmful
immune response. But I think there are a lot
of solutions to this potential problem and
if people are interested we can talk about
those later.
In the last few minutes of my talk, I’m
going to give you my view about genome editing
of humans and the shoulds and should nots.
This idea of genome editing of humans is not
conceptually a new idea; the idea of genetic
engineering of humans of course has been around
for hundreds of years if not at least 50 years
and it’s the subject of books and bioethical
essays, and movies, and so on and so forth.
People have divided this into this 2x2 box
where one can think about somatic cell editing
to treat or prevent disease. We can talk about

English: 
RECOGNIZES THE GENOME TOOL WE
HAVE BEEN WORKING ON.
>>> IT WILL BE DIFFICULT TO GIVE
THIS TO GENTLEMAN MODEM
PATIENTS.
>>> IF WE TRIED TO GIVE CAST 9
TO GIVE ENVY VOW, INSIDE THE
BODY, WE COULD POTENTIALLY CAUSE
HARM.
IF PEOPLE ARE INTERESTED, WE CAN
TALK ABOUT THAT LATER.
>>> IN THE LAST FEW MINUTES OF
MY TALK, I WILL GIVE YOU THE
SHOULD, AND SHOULD-NOTES.
>>> IT IS NOT CONCEPTUALLY A NEW
IDEA, THE GENEICLY HAS BEEN
AROUND FOR HUNDREDS OF YEARS,
AND SUBJECT OF BOOKS, AND
ESSAYS, AND MOVIES AND SEW ON
AND SO FORTH.

English: 
germline or heritable editing for the treatment
of disease or the prevention of disease, somatic
cell editing for enhancement, and germline
and heritable editing for enhancement. Now
that we have the ability to do editing so
well, the question is which of these four
boxes should we apply it to?
I was fortunate enough to participate on a
committee, an international study committee
sponsored by the National Academy of Sciences,
National Academy of Medicine, called the Committee
on Human Gene Editing Scientific Medical and
Ethical Considerations, and Professor Charo
was actually the chair of that committee.
That’s where I got to know her very well
and for those of you interested here’s a
website and actually in Professor Charo’s
presentation you’ll see it as well. I’m
going to go through a little bit about what
the committee thought, but I’m going to
take you through what this committee prompted
me to think about. Which is what were the

English: 
>>> IT IS SORT OF THE THOUGHT
PROCESS, PEOPLE WIDED THIS INTO
A 2 BY 2 BOX.
WHERE ONE CAN TALK ABOUT SOMATIC
EDITING, OR GENOME EDITING FOR
THE PREVENTION OF DISEASE.
SOMATIC FOREIGN HANSMENT, AND
GENTLEMAN GNOME FOREIGN
HANSMENT.
>>> NOW WE HAVE ABILITY TO DO
EDITING SO WELL, THE QUESTION
IS, WHICH OF THE FOUR BOXES
SHALL WE APPLY IT TO.
I WAS INVITED BY THE NATIONAL
ACADEMY OF SCIENCES, CALLED
HUMAN GENE EDITING, AND
PROFESSOR CHARO WAS ACTUALLY THE
CHAIR OF THAT COMMITTEE.
FOR THOSE OF YOU INTERESTED
HERE'S A WEBSITE, AND PROFESSOR

English: 
important ethical principles that I would
use to evaluate which potential applications
of genome editing we should, which would be
the ethical applications of genome editing
in my own mind? These were the six principles
that I came up with. Actually it was very
interesting for me to think through this.
The first is a concept from John Rawls about
the veil of ignorance. What he’s writing
about here is to think about what world would
you want if you didn’t know where into that
world you would be born. I happen to be healthy
and not have a genetic disease, but what if
I didn’t know that? What sort of world would
I want if I might be born into this world
with sickle cell disease or Huntington’s
disease or cystic fibrosis? I’m an MD and
maybe I’m a little TMI here. I don’t know
if I can really recognize what happiness is,
but as an MD I think I can recognize what
suffering is. I think we have a duty to minimize
suffering. I think we also have a duty to

English: 
CHARO'S PRESENTATION, AS WELL.
>>> I WILL GO THROUGH WHAT THE
COMMITTEE THOUGHT, BUT WHAT
PROMPTED ME, WHAT ARE THE
PRINCIPLES I WOULD EYES FOR
GENOME EDITING, WHAT WOULD BE
THE ETHICAL APPLICATIONS IN MY
OWN MIND.
>>> THESE ARE THE SIX PRINCIPLES
I CAME UP WITH.
IT WAS VERY INTERESTING FOR ME
TO THINK THROUGH THIS.
>>> THE FIRST IS A CONCEPT FOR
JOHN RAVES ABOUT THE VEIL OF
IGNORANCE.
HAVE TO THINK ABOUT WHAT WORLD
WOULD YOU WANT IF YOU DIDN'T
KNOW WHERE INTO THE WORLD YOU
WOULD BE BORN.
>>> I HAPPEN TO BE HEALTHY AND
NOT HAVE A GENETIC DISEASE.
BUT IF IF I DIDN'T KNOW THAT, OR
MAYBE I WAS BORN WITH
SICKLE-CELL, OR HUNTINGTON'S,

English: 
minimize structural inequality. That doesn’t
mean that there will be no inequality. It
just means we shouldn’t create a society
in which inequality is sort of baked into
the cake. John Evans who is a sociologist
and bioethicist at UCSD highlighted to me
that we have to be careful that when we’re
editing peoples’ DNA, we don’t convert
them into objects. That we don’t treat their
DNA as the individual. Instead, that we maintain
people as humans. I think we also need to
recognize that we need to be humble about
how much we do or don’t know, particularly
as it relates to genetics. Very simple to
think well we understand this or that, but
I think in reality we understand very little
about human genetics. We need to recognize
our lack of knowledge. Finally, I think diversity
is strength. I mentioned earlier that thank
God we’re all different. One of the things

English: 
AND I AM A MD, MAYBE TOO MUCH,
TMI, BUT I CAN RECOGNIZE WHAT
SUFFERING IS, AND I THINK WE
HAVE A DUTY TO LESSON SUFFERING,
AND STRUCTURAL INEQUAL TEE, WE
SHOULDN'T CREATE A SOCIETY WHERE
INQUALITY AT THIS IS BAKED INTO
THE CAKE.
>>> JOHN EVANS WHO IS A
SOCIOLOGIST, HIGHLIGHTED TO ME,
WE HAVE TO BE CAREFUL WHEN WE
ARE EDITING PEOPLE'S DNA WE
DON'T CONVERT THEM INTO OBJECTS.
THAT WE DON'T TREAT THEIR DNA AS
THE INDIVIDUAL.
>>> INSTEAD, WE MAINTAIN PEOPLE
AS HUMANS.
AS HUMANS.
>>> I THINK WE ALSO NEED TO
RECOGNIZE, WE NEED TO BE HUMBLE
HOW MUCH WE DO OR DON'T KNOW,
PARTICULARLY WILL RECALL --
PARTICULARLY AS IT RELATES TO
GENETICS.
I THINK IN REALITY WE UNDERSTAND
VERY LITTLE ABOUT HUMAN

English: 
GENETICS, AND WE NEED TO REALIZE
OR LACK OF KNOWLEDGE.
>>> FINALLY, I THINK DIVERSITY
IS OUR STRENGTH.
THANK GOD WE ARE ALL DIFFERENT.
>>> WHAT ANNOYS ME, COVERS OF
MAGAZINES, HUMAN GENOME EDITING,
AND THEY SHOW A PICTURE OF A
WHITE, BLONDE-HAIRED, BLUE-EYED
BABY BOY.
THOSE ARE PICTURES I THINK WE
SHOULD PUSH AGAINST.
>>> HOW WE SHOULD USE GENOME
EDITING ON HUMANS.
OBVIOUSLY, I AM WORKING ON
SICKLE-CELL, SO I AM USING IT
FOR DISEASE.
>>> I ALSO -- I MENTIONED
SICKLE-CELL IN THE U.S., LIVE
LONGER THAN THOSE IN AFRICA.

English: 
that kind of annoys me, not kind of, really
annoys me is when I see covers of magazines
stating human genome editing is here, engineering
humanity and they show a picture of a blonde
hair, blue eyed, white baby boy. I think there
are a lot of implications of that picture
that are, I think we should push against.
Using these six personal principles, how do
I come down on how we should use genome editing
of humans? So obviously I’m working on sickle
cell disease so I think there are a lot of
greens in terms of using somatic cell editing
for disease. I do think there’s a yellow
though about minimizing inequality. I already
mentioned that patients with sickle cell disease
in the US live much longer than patients with
sickle cell disease in Africa. If we’re
going to develop advance therapies how do
we make sure that these get distributed to
all the people in the world who could benefit
from them. I think there are many reasons
why somatic cell editing for enhancement should

English: 
>>> HOW DO WE MAKE SURE THESE
GET DISTRIBUTED TO ALL THE
PEOPLE IN THE WORLD WHO WILL
BENEFIT FROM THEM.
>>> I THINK FOREIGN HANSMENT
SHOULD NOT BE DONE.
I WILL HIGHLIGHT, THERE IS A
GROUP OF OF PEOPLE OUT THERE,
CALLING THEMSELVES, TRANCE
HUMANISTS, WHO BELIEVE HUMANS,
OR A FLAWED SPECIES, AND IT IS
OUR OBLIGATION TO USE ALL
THOSE
TOOLS TO -- I WILL GO INTO THIS
MORE IN THE NEXT HALF HOUR.
>>> OUR COMMITTEE MADE A CHANGE
FROM THE PAST, WE SAID, UNDER
VERY SPECIFIC CIRCUMSTANCES, ONE
MIGHT CONSIDER USING MERITBLE
EDITING FOREIGN HANSMENT.
FINALLY HEARTHBLE EDITING
FOREIGN HANSMENT, IT IS HARD TO

English: 
not be done. I think they violate many of
these principles. I will highlight that there
is a field, a group of people out there who
call themselves transhumanists who believe
that humans are a fundamentally flawed species
and that it is our ethical obligation to use
every tool at our disposal to solve those
flaws. I am not a transhumanist but there
are people out there. I’ll go into this
a little bit more in the next half hour but
our committee made a little change from the
past where we said under very specific circumstances
one might consider using heritable editing
for disease. I’ll talk about that in more
detail in the next half hour. Finally, heritable
editing for enhancement, it’s hard to see
any benefit from that.
I’m going to skip through these slides because
I’ll go through them with Professor Charo’s
talk, but I think in summary Barry Coller

English: 
SEE FOR THAT.
>>> I WILL SKIP THROUGH THE
SLIDES.
>>> BUT, IN
SUMMARY, BARRIE
COLOR, CAME UP, HE SAID, WE
SHOULD BE MAKING HEALTHY BABIES
NOT DESIGNER BABIES, AND I
PARAPHRASED THAT, WE SHOULD BE
USING IT TO MAYBE HEALTHY
BABIES --
[INDISCERNIBLE]
>>> SO, IN MICE, AS SOME OF YOU
HEARD EARLIER TODAY, IT IS A
BROADLY RESEARCHED TOOL.
IT IS A FANTASTIC WAY OF MAKING
GENETICALLY ENNEAD MICE,
INCLUDING MODELLING OF HUMAN
DISEASE.
>>> IT HAS BEEN USED IN NON-
NON-HUMAN PRY MATES.
THERE HAVE BEEN DEFINITELY A
SMALL NUMBER BORN.
FOR EVERY HUNDRED EMBRYOS, THAT

English: 
who is one of the committee members and the
Chief Medical Officer at Rockefeller said
we should be making healthy babies not designer
babies, and I have paraphrased that to say
we should be using genome editing to make
healthy humans not designer humans and I really
like that saying.
Finally, what is the current status of genome
editing of embryos? In mice and as some of
you heard earlier today, it’s a broadly
utilized research tool. It’s a fantastic
way of making genetically engineered mice
to study a wide variety of processes including
modeling of human disease. It’s been used
in nonhuman primates and there have definitely
been a small number of animals born, but the
efficiency is quite low. So for example, for
every 100 embryos or zygotes that get injected
with the genome editing machinery, only 1
or 2% of those will actually be born. And
then I think there’s a separate ethical
issue about whether we should be engineering

English: 
nonhuman primates to mimic human diseases
because of course those animals will be suffering.
In terms of humans, there have been sort of
3 major published studies – two out of China,
one out of Oregon. The studies out of China
used tripolar zygotes. These are in vitro
fertilized embryos that have 3 nuclei in them
and so are nonviable and will quickly die
and disintegrate within the first week of
life. The Chinese investigator showed that
they could use the CRISPR/Cas9 tool to create
genetic edits in these nonviable human zygotes
but that was inefficient and they saw significant
off-target effects. But as we mentioned, probably
those off-target effects will go away. More
recently a study out of Oregon showed that
they were actually trying to edit viable human
zygotes for an autosomal dominant heart disease

English: 
GET INJECTED WITH GENTLEMAN
MODEM EDITING,
ONLY FEW ARE
BORN.
>>> AND USING PRIMATES TO MIMIC
HUMAN DISEASES, BECAUSE OF
COURSE, THOSE ANIMALS WILL BE
SUFFERING.
>>> THERE ARE TWO PUBLISHED
STUDIES.
THE STUDIES OUT OF
CHINA, USED
SIGHING GOATS.
THEY HAVE THREE NUCLEI IN THEM.
THEY ARE
NON-VIALBLE, AND
DISSINK GREAT EARLY IN LIFE
AS
WE MENTIONED, PROBABLY THOSE OFF
TARGET AFFECTS WILL GO AWAY.
>>> MOST RECENTLY OUT OF OREGON,

English: 
and again, what they showed is that it remains
technically inefficient and as I’ll go to
in the next half hour, the disease they picked
was inconsistent with the criteria that we’ve
outlined that one might consider doing genome
editing of zygotes for heritable or germline
editing. Moreover the results are actually
quite scientifically controversial. There
are many people in the field who feel like
what they published was an artifact. With
that, I’m going to end my half hour. I’m
going to take a sip of water and try to channel
Alta Charo and talk to you about some of the
ethics and legal basis and regulatory aspects
of genome editing.
So, Jennifer Doudna is shown here and Alta
started with this slide because Jennifer had
a quote saying we may be nearing the beginning

English: 
SHOULD THEY WERE TRYING TO HE
HAD DID I TELL VIABLE
SIOUX
GOATS, AND THE DISEASE THEY
PICKED WAS INCONSISTENT WITH THE
CRITERIA WE HAVE OUTLINED THAT
ONE MIGHT CONSIDER DOING
EDITING.
MOREOVER, THE RESULTS ARE QUITE
SCIENTIFICALLY CONTROVERSIAL,
AND MANY PEOPLE IN THE FIELD
THINK WHO THEY PUBLISHED WAS AN
ART FACT.
>>> I WILL END MY HALF HOUR,
TAKE A SIP OF WATER, AND TRY TO
CHANNEL ALTA CHARO, AND TALK TO
YOU SOME OF THE ETHICS AND LEGAL
BASIS OF GENOME EDITING.
[APPLAUSE]
>>  ALL RIGHT, YOU CAN DO THAT,
TOO.

English: 
OKAY.
JENNIFER DOWN HAS SHOWN HERE,
AND ALTA STARTED WITH THIS
SLIDE, BECAUSE JENNIFER HAD A
QUOTE, SAYING WE MAY BE NEAR THE
ENDING OF GENETIC DISEASES.
I THINK THAT IS OPTED MYSTIC.
NONETHELESS, THERE IS OPT ITEM
OF USING GENOME EDITING, BUT
THERE HAS BEEN FEARS ABOUT IT,
AS I HAVE HIGHLIGHTED, ARE WE
GOING TO USE IT IN WAYS WE
DIDN'T INTEND.
>>> BECAUSE OF THAT, THE
NATIONAL ACADEMY OF SCIENCES,
AND ACADEMY OF MEDICINE, MADE A
COMMITTEE, TO EVALUATE, THE
SCIENCES OF GENOME EDITING, AND
ETHICAL AND LEGAL STANDARDS, CAN
WE DEVELOP ANY OVER AMPING, AND
WHAT WERE THE PROSPECTS FOR
NATIONAL COORDINATION?

English: 
of the end of genetic diseases. I think that’s
rather optimistic, but nonetheless there is
incredible optimism about the use of genome
editing, hopefully I’ve conveyed why we’re
so optimistic, but there has also been a lot
of fears about it because, as I’ve sort
of highlighted, are we going to use it in
ways we didn’t intend?
Because of that, the National Academy of Sciences
and National Academy of Medicine, as I said,
convened an international committee to evaluate
the state of the science of genome editing,
the potential for clinical applications, ethicolegal
and regulatory standards. Do we develop any
overarching principles for regulation? What
were the prospects for international coordination?
What was great about this committee is that
it was broad, not only in terms of where people
were from - US, and Canada and Israel and
Egypt and France and England and China, I’m

English: 
missing a few and broad in expertise – lawyers,
bioethicists, pediatricians, scientists – a
whole range of different people. The way the
committee functioned is that it met multiple
times both in the US and overseas and invited
the broadest range of stakeholders we could
imagine to come and talk to us about what
they thought were the key issues in terms
of using human genome editing. Out of that
process came this report that’s available
online for free. Again, these slides are going
to be available so you can find it quite easily.
There are 3 major applications of genome editing.
The first is to use it as a basic research
tool in the laboratory to work on cells and
tissues. The second are again, what I alluded
to earlier in terms of somatic cell editing
for patients or germline editing to treat
or prevent disease.
Now in terms of basic research, which I didn’t

English: 
>>> WHAT WAS GREAT ABOUT THIS
COMMITTEE, IT WAS BROAD, IN
TERMS OF WHERE EVERYONE WAS
FROM, THEY BROUGHT IN EXPERTISE,
LAWYERS, PEDIATRICIANS,
SCIENTISTS, YEAH, SO A HOLE
RANGE OF DIFFERENT PEOPLE.
AND THE WAY THE COMMITTEE
FUNCTIONED, IT MET MULTIPLE
TIMES BOTH IN THE U.S. AND
OVERSEAS, AND THEY CAME TO TALK
TO USES ABOUT WHAT THEY THOUGHT
WERE THE KEY ISSUES IN TERMS OF
USING HUMAN GENOME EDITING.
AND CAME IS THIS REPORT ONLINE
FOR FREE.
>>> SO, THERE IS THREE MAJOR
APPLICATIONS OF GENTLEMAN MODEM
EDITING.
FIRST TO USE IT AS A BASIC TOOL
IN A LABORATORY.
AND SECOND, AGAIN, WHAT I

English: 
discuss very much before, one can imagine
using genome editing of somatic cells, of
germline cells, of pleuripotent cells, so
ES cells and iPS cells, as a way of better
understanding how genes function, the differences
between mouse and human, how human fertility
and early embryonic development works, the
links between genes and disease, the progression
of disease with strong or even weak genetic
components. The uses are not endless but they’re
broad and they’re important and the tool
has been adopted very broadly.
But luckily there are already many regulations
into this type of research ranging from institutional
biosafety committees which focus on laboratory
safety, institutional review boards to make
sure that people are doing research that’s
consistent with privacy and interests in terms
of tissues and cells, and then there’s the
NIH Recombinant DNA Advisory Committee. There

English: 
ALLUDED TO EARLIER IN TERMS OF
SO MATIC CELLS ON PATIENTS, OR
TO TREAT AN OR PREVENT DISEASE.
>>> IN TERMS OF RESEARCH, WHICH
I DIDN'T DISCUSS BEFORE.
ONE CAN IMAGINE USING GENTLEMAN
GNOMIC EDITING AS A WAY OF
BETTER UNDERSTANDING HOW GENES
FUNCTION, THE DIFFERENCES
BETWEEN HOUSE MOUSE AND HUMAN.
HOW EARLY FERTILITY WORKS.
THE LINKS BETWEEN DISEASE AND
WEAK GENEIC COMPONENTS.
SO, THE USES ARE NOT ENDLESS,
BUT THEY ARE BROAD.
>>> THE TOOLS HAVE BEEN ADOPTED
VERY BROADLY.
>>> LUCKILY, THERE ARE ALREADY
MANY REGULATIONS IN THIS
RESEARCH.
BIO SAFETY COMMITTEES,
INSTITUTIONAL REVIEW BOARDS TO
MAKE SURE THAT PEOPLE ARE DOING
RESEARCH THAT IS CONSISTENT WITH

English: 
is already in the US a regulatory oversight
to the use of genome editing for research
purposes.
One says well what about embryos? The use
of embryos in research is not restricted to
genome editing. People use those for other
types of research using other tools as well.
Those are also regulated in different ways,
so certain states prohibit the use of embryos
in research. There are limitations on the
amount of federal funding you can get, and
there are issues of where you can get those
embryos from. There are definitely different
public attitudes about working with embryos.
So, Alta’s advice for scientists is to make
sure you’re aware of your institutional
policies; make sure you keep your funding
streams, you understand your funding streams
so you are using the right monies for embryo
research; make sure your embryos are coming

English: 
PRIVACY AND INTEREST IN TERMS OF
TISSUE AND CELLS.
AND THEN THERE IS THE ADVISORY
COMMITTEE.
SO, THERE IS AN OVERSIGHT FOR
GENOMIC EDITING RESEARCH.
>>> THE USE OF EMBRYOS IN
RESEARCH IS NOT RESTRICTED TO
GENOME EDITING.
PEOPLE DON'T RESTRICT FOR OTHER
TOOLS, AS WELL.
THEY ARE ALSO REGULATE THE IN
DIFFERENT WAYS.
CERTAIN STATES PROHIBIT THE USE
OF EMBRYOS ON RESEARCH.
LIMITED FUNDING YOU CAN GET.
AND ISSUES WHERE YOU CAN GET THE
EMBRYOS FROM.
>>> THERE IS DEFINITELY
DIFFERENT PUBLIC ATTITUDES ABOUT
WORKING WITH ATTITUDES.
SO, ALTA'S ADVICE FOR
SCIENTISTS, MAKE SURE YOU ARE
AWARE OF INSTITUTIONAL POLICIES.

English: 
YOU UNDERSTAND YOUR FUNDING
STREAMS, SO YOU ARE USING THE
RIGHT MONIES FOR EMBRYO
RESEARCH.
MAKE SURE THEY ARE COMING FROM
AN ETHICALLY SOURCE.
AND TO HAVE TRANSNATIONAL
COLLABORATIONS, BECAUSE THE
GUIDELINES MAY NOT BE YOURS.
>>> IN GERMANY RESEARCHERS ARE
PROHIBITED ON WORKING ON
EMBRYOS, AND IN FACT, A GERMAN
CITIZEN WORKING ON EMBRYOS,
OUTSIDE OF GERMANY, CAN STILL BE
ARRESTED.
>>> I AM NOT GERMAN.
>>> THAT'S FOR RESEARCH.
IT'S A GREAT TOOL, IT WILL
ADVANCE OUR UNDERSTANDING OF
HUMAN DISEASE, AND BASIC
MECHANISMS, BUT WITH A PRETTY
WELL ESTABLISHED OVERSIGHT
MECHANISM.
>>> NOW, THINKING ABOUT SOMATIC
GENE THERAPY, AND GENOME GENE
THERAPY.

English: 
from an ethically permissible source; and
have special considerations for transnational
collaborations because the guidelines of one
country may not be the guidelines of yours.
A dramatic point of this is actually in Germany
where researchers are prohibited from working
on embryos and in fact a German citizen who
works on embryos outside of Germany can still
be arrested. I’m not German.
That’s for research. Again, it’s a great
tool. It will advance our understanding of
human disease and basic mechanisms, but with
a pretty well established regulatory oversight
mechanism. Now what about thinking about in
terms of somatic cell gene therapy and germline
gene therapy?
So again, going back to somatic cell gene
therapy, they will go into somatic cells which
will not be inherited in later generation
whereas germline therapy would be introducing

English: 
changes into cells that could be passed along
to future generations. In the US, germline
gene therapy is currently not being attempted,
but what would stop us from doing that?
In terms of somatic cell gene therapy, or
somatic cell editing, which again I haven’t
said but I should point out, somatic cell
gene editing is really just a form of gene
therapy. Because gene therapy has been around
as a field for over 30 years, there’s a
well-developed oversight mechanism for how
gene therapy needs to occur in the US. Again,
this occurred through institutional biosafety
committees, institutional review boards, the
Recombinant DNA Advisory Committee, and last
but certainly not least is the Food and Drug
Administration. Before any somatic cell gene
therapy, before any genetically manipulated
cell or tissue is introduced into a human
being, you have to have approval from the

English: 
IN THE U.S.
GENOME THERAPY -- IN
TERMS OF SOMATIC CELL EDITING, I
HAVEN'T SAID, BUT POINT OUT, IT
IS REALLY JUST A FORM OF OF GENE
THERAPY.
BECAUSE GENE THERAPY HAS BEEN
AROUND IN A FIELD FOR OVER 30
YEARS, THERE IS A WELL-DEVELOPED
OVERSIGHT MECHANISM HOW IT NEEDS
TO OCCUR IN THE U.S.
AGAIN, THIS OCCURS IN
INSTITUTIONAL BIO SAFETY
COMMITTEES.
AND ADVISORY COMMITTEE, AND LAST
BUT NOT LEAST, IS THE FOOD AND
DRUG ADMINISTRATION.

English: 
>>> BEFORE ANY SOMATIC GENE
CELL, OR GENICALLY MANIPULATED
CELL IS INTRODUCED TO A HUMAN
BEING, YOU HAVE TO HAVE APPROVAL
BY THE FD, A.
IF YOU DO NOT, IT IS AGAINST THE
LAW.
>>> THEY PROVIDE A A POINT AT
WHICH BEFORE I CAN INTRODUCE A
CELL, THAT HAS BEEN GENETICALLY
MA MY OPINION LATED, THE FDA HAS
TO REVIEW WHAT I HAVE DONE, AND
DEEMED IT THE RISK BENEFIT
ANALYSIS AS BEING WORTH TRYING.
>>> AND THEY ALSO CONTROL OVER
FUNCTIONAL APPROVAL AS A DRUG.
>>> THE ONE WEAKNESS -- OR TWO
FDA HAS, BYLAW, THEY CAN'T
DISCLOSE WHAT THEY HAVE TALKED
ABOUT WITH ONE GROUP.
SO IF I TALK TO THEM, THEY
CANNOT DISCLOSE TO ANOTHER GROUP

English: 
FDA. If you do not have approval from the
FDA, it is against the law. So they provide
a bottleneck. I won’t say bottleneck. They
provide a point at which before I can introduce
a cell that’s been genetically manipulated
either in vivo or ex vivo, the FDA has to
review what I’ve done and deemed the risk
benefit analysis as being worth trying. And
they also control over functional approval
as a drug. The one weakness that the FDA has,
well there are two weaknesses. One is by law
they can’t disclose what they've talked
about with one group. If I go in and talk
to them about my genome editing procedure,
they cannot disclose to another group what
they talked to me about. There’s a lack
of transparency there. The second thing that
the FDA has, there’s a bit of a weakness

English: 
WHAT THEY TALKED TO ME ABOUT.
THE SECOND TRANSPARENCY THE FD,
A HAS, A BIT OF A WEAKNESS, THEY
ARE NOT ALLOWED TO EVALUATE THE
SCIENTIFIC COMPLICATIONS BUT A
RISK-BENEFIT ANALYSIS.
>>> SO, THE FDA, IF THEY FEEL
LIKE THEY NEED ETHICAL ADVICE,
THEY WILL ASK TO REVIEW A
PROTOCOL, BECAUSE THEY ARE
LEGALLY NOT ALLOWED TO DO THAT.
SO, IT IS PROBABLY NOT RIGHT.
>>> IN TERMS OF BASIC RESEARCH,
AND SOMATIC CELL THERAPY,
PARTICULARLY, SOMATIC CELL
THERAPY, IT ALREADY FALLS UNDER
EXISTING NORMS, AT THE LOCAL
STATE AND FEDERAL LEVELS.
FROM THAT, THE FD, A HAS MADE IT
CLEAR, THEY WILL LIMIT CLINICAL
TRIALS, TO PREVENTION OF DISEASE
AT THIS TIME.

English: 
here is that they’re not allowed to evaluate
the ethical implications of the research.
They’re only allowed to do a risk benefit
analysis. The Recombinant DNA Advisory Committee
contains ethicists. So the FDA, if they feel
like they need ethical advice, will ask the
Recombinant DNA Advisory Committee to review
a protocol because they are legally not allowed
to do that. It’s probably not right.
So, in terms of basic research and somatic
cell therapy, well particularly somatic cell
therap,y as I said it probably already falls
under existing norms and regulatory regimes
at the local, state, and federal levels and
from that the FDA has made it clear that they
were going to limit clinical trials or therapies
to treatment and prevention of disease or
disability at this time. The important thing
is because this field is moving so quickly,
that last bullet point is that there is probably

English: 
at this point no way to establish a single
standard. There’s no way to say this is
safe enough for that disease or one standard
says that you need to hit this level of safety
for all diseases, that every indication will
have to be evaluated on its own merits. Now
perhaps in the future and I know actually
the National Institute of Standards is working
on establishing a set of benchmarks that people
can target but those are not in place and
probably not appropriate to put in place until
we learn more.
What about then enhancement? So enhancement
can mean a lot of things. It can mean enhancing
our ability to resist disease. It can perhaps
mean allowing us to digest gluten or those
of us who are lactose intolerant or gluten
intolerant. It could mean enhancing human
traits like muscle mass or characteristics
like perfect pitch or longevity or intelligence.

English: 
THE IMPORTANT THING, BECAUSE
THIS FIELD IS MOVING SO QUICKLY,
THERE IS PROBABLY AT NO POINT TO
ESTABLISH A SINGLE STANDARD.
THERE IS NO WAY TO SAY THIS IS
SAFE ENOUGH FOR THAT DISEASE.
OR ONE STANDARD, YOU NEED TO HIT
THIS LEVEL OF SAFETY FOR THIS
DISEASE.
EVERYTHING WILL HAVE TO BE BASED
ON THEIR OWN MERITS.
THEY ARE WORKING ON A SET OF
BENCHMARKS FOR THE TARGET.
BUT THEY ARE NOT IN PLACE.
>>> WHAT ABOUT ENHANCEMENT.
SO ENHANCEMENT CAN MEAN A LOT OF
THINGS.
IT CAN MEAN ENHANCING OUR
ABILITY TO RESIST DISEASE.
IT COULD PERHAPS MEAN ALLOWING

English: 
DIGEST GLUTEN, OR THOSE OF US,
WHO ARE LACTOSE INTOLERANT OR
GLUTEN INTOLERANT.
ENHANCING HUMAN TRAITS, LIKE
MUSCLE MASS OR PERFECT PITCH, OR
LONGEVITY OR INTELLIGENCE.
I POINT OUT, MOST OF THE TRAITS
ARE NOT -- IN FACT, ALL OF OF
THESE ARE NOT SINGLE GENE
TRAITS.
IT WOULD CHALLENGING TO THINK
HOW TO EVEN DO IT.
>>> AND THEN THE POSSIBILITY OF
NON-HUMAN TRAITS.
>>> WHAT WE MEAN BY ENHANCEMENT,
IS MAKING HUMAN CAPACITIES.
>>> WOULD THIS BE AVAILABLE TO
ONLY SOME PEOPLE?
PRESSURE ON PEOPLE TO SEEK OUT
ENHANCEMENTS?
WE CERTAINLY DO ENCOURAGE
ENHANCEMENTS IN OUR SOCIETY
AROUND ENHANCEMENT THROUGH GOOD
NUTRITION, AND EDUCATION, AND
ENHANCEMENT THROUGH COSMETIC
PROCEDURES.

English: 
Although I’ll point out that most of the
traits we put here are not single gene, in
fact I would say all of these are not single
gene traits and it would be very challenging
to think about how we’d even do it. And
then the possibility of engineering nonhuman
traits into humans.
So again, what we mean by enhancement is making
changes beyond ordinary human capacities.
What are some concerns about fairness? Would
this only be available to some people? Would
there be pressure on people to seek out enhancements?
We certainly do encourage enhancements in
our society around enhancement through good
nutrition, enhancement through education,
enhancement through cosmetic procedures. Some
people even call vaccines enhancements because
they’re enhancing our immune system. I would
argue a vaccine is not enhancing our immune
system it’s being used to prevent a disease,

English: 
SOME PEOPLE CALL VACCINES
ENHANCEMENT.
I WOULD ARGUE IT IS NOT
ENHANCING, BUT USED TO PREVENT A
DISEASE.
NONETHELESS, PEOPLE HAVE POINTED
IT OUT.
>>> THE OTHER THING, WHAT IF I
DEVELOP A MUSCULAR GENOME
EDITING PROCEDURE, FOR MUSCULAR
DISFEE, BUT THE ANALOGY, THE
GROWTH HOAR MOAN WOULD TREAT
UNDERLYING DISEASE CONDITIONS,
AND NOW UNFORTUNATELY, THEY HAVE
BEEN REPURPOSED BY ATHLETES AND
OTHER TO ENHANCE THEIR TRAITS.
>>> WHAT WAS THE COMMITTEE'S
RECOMMENDATIONS FOREIGN
HANSMENTS.

English: 
but nonetheless people have pointed that out.
Then the other issue is what if I develop
a genome editing procedure that is used to
treat muscular dystrophy but it’s repurposed
to make muscle mass say of a non-muscular-dystrophy
patient bigger. The analogy would be erythropoietin
or growth hormone was developed to treat underlying
disease conditions and now unfortunately they’ve
been repurposed by athletes and others to
enhance their traits.
So what were the committee’s recommendations
on enhancement? That editing for purposes
other than treatment or prevention of disease
should not proceed at this time, that an enhancement
is unlikely to offer benefits sufficient to
offset risk at this time. The challenge is
what if in 10 years we find genome editing
is incredibly safe. Does that mean we still
shouldn’t be enhancing? I think that we
still shouldn’t, but if you took risk off

English: 
>>> THE FINAL BULLET POINT THE
COMMITTEE RECOMMENDED, THAT
ENHANCEMENT, SO WHILE I AM PROUD
THE COMMITTEE WAS
DIVERSE,
.
>>> HER VISES TO COLLIN IN
ADDITIONS, AND PREVENTION TO
ENHANCEMENT, THAT WE DISTINGUISH
INKNOW ELEVATOR THERAPY, AND
MEDICAL PRACTICE FROM USE OF A
FDA CELL-BASE PRODUCT, AND AN
USING CELLS TO REGENERATE ORGANS

English: 
the tablet would then that open the door to
people using it for enhancement? Then the
final bullet point was that the committee
recommended that enhancement should not be
done without extensive public input. So while
I’m proud that the committee was broad and
diverse, it was only 22 people and that’s
clearly not a big enough group to make a decision
like this. So what many groups including the
National Academies are doing is continuing
to support an ongoing discussion.
So her advice to clinicians is to make sure
we distinguish therapy from prevention from
enhancement; that we distinguish innovative
therapy from research; that we distinguish
medical practice from use of an FDA-regulated
cell-based product; and that there’s an
interplay with regenerative medicine so using
cells to regenerate organs that have not been
genetically enhanced.
Moving now on to heritable genome editing.
As I mentioned, this has been achieved in

English: 
animals and is a powerful research tool. It
can be done in a number of different ways.
One is to use the directly injected genome
editing machinery into a zygote, so after
the sperm meets the egg do the editing at
that stage. The problem with that is that
you don’t get to analyze that zygote. You
get what you get and if you pull out one cell
and analyze that you don’t know if that
predicts what’s going on in another cell.
The other way that one could do heritable
editing though is not to edit the zygote,
but edit the cell that gives rise to the sperm
or edit the cell that gives rise to the egg
and then create a zygote from the edited sperm
or egg. Now you could characterize the stem
cell that gives rise to the egg or gives rise
to the sperm characterize it and use that.
So that has been done in mice, but it has
not been done in humans. When you think about
heritable editing, it’s not all about embryo
or zygote editing. You could do heritable

English: 
THAT HAVE NOT BEEN GENETICALLY
ENHANCED.
NOW MOVING TO GENOME EDITING,
FOR THE PURPOSES OF TREATMENT OR
PREVENTION.
AFTER THE SPERM MEETS THE EGG,
DO THE EDITING AT THAT STAGE.
>>> THE PROBLEM WITH THAT, IS
THAT YOU DON'T GET -- IF YOU
PULL OUT ONE CELL, YOU DON'T
KNOW IF THAT PREDICTS THAT IS
GOING ON IN ANOTHER CELL.
THE OTHER WAY TO DO INHERITING,
EDIT THE CELL THAT GIVES RISE TO
AT A EGG, AND CREATE A SIGHING
GOA FROM THE SPERM TO THE EGG.
NOW YOU CAN CHARACTERIZE THAT
GIVES RISE TO THE EGG OR SPERM,
AND CHARACTERIZE IT AND USE
THAT.

English: 
editing without manipulating zygotes or embryos.
So why would one want to do heritable genome
editing for disease? Many of those 10,000
genetic diseases I mentioned, it’s possible
that somatic cell editing just won’t work.
The disease might occur in utero before we
can intervene. So then John Evans would say
if that’s the case, is there an ethical
right to having genetically-related children?
He didn’t believe it but other people, obviously

English: 
THAT HAS BEEN DONE IN MICE, BUT
HAS NOT BEEN DONE IN HUMANS.
WHEN YOU THINK OF HEARTHBLE
EDITING, IT IS NOT ALL ABOUT
SIGH GOATS -- YEAH, I THINK THIS
IS SUMMARY OF WHAT A LOT OF
THINGS I SAID.
>>> SO, WHY WOULD ONE WANT TO DO
HEARTHBLE GENOME EDITING FOR
DISEASE?
>>> SO, THERE ARE MANY OF THOSE
THOUSANDS OF GENETICALLY, THOSE
10,000 GENETIC DISEASE I
MENTIONED, IT IS POSSIBLE IT
WON'T WORK.
THE DISEASE MAY OCCUR IN YOUTH
ROW BEFORE WE CAN INTERVENE.
JOHN EVANS WOULD SAY, IF THAT'S
THE CASE, WHY -- IS THERE AN
ETHICAL RIGHT TO HAVE

English: 
if you watch how people behave they do. There
is a small number of examples where you could
imagine that the only way to treat or prevent
a disease is by doing it very, very early
and you couldn’t do it later.
So what are the concerns? Of course off-target
changes or genetic changes may be inherited
by the next generation and the possible of

English: 
GENETICALLY RELATED CHILDREN?
UM, YOU KNOW, HE DIDN'T BELIEVE
IT, BUT OTHER PEOPLE --
OBVIOUSLY, IF IF YOU WATCH HOW
PEOPLE BEHALF, THEY DO.
>>> SO, THERE IS -- SO, THERE IS
A SMALL NUMBER OF EXAMPLES,
WHERE YOU WOULD IMAGINE THE ONLY
WAY TO TREAT A DISEASE IS DOING
IT VERY EARLY, BECAUSE AS SOON
AS -- AND YOU COULDN'T DO IT
LATER.
>>> SO, I WILL SKIP AHEAD, AND
JUST SAY, OBSERVING, OKAY,
YEAH.
WOE, WHERE AM I GOING?
WHAT DID I JUST DO?
[LAUGHTER]

English: 
multigenerational risks the real difficulty
of any long term followup; issues that we
talked about today about who’s giving consent
for this – the child is somebody who never
gave consent to being genetically edited;
and then the risk that we’re going down
a slippery slope and if we’re using this
to engineer, to do editing for disease, would
somebody now start to do this for enhancement?
The committee came to the conclusion that
caution is needed but caution does not mean
prohibition. We propose that heritable editing
for treatment of serious disease might be
permitted but only after a number of very
specific criteria were met. First was that
we need much more research to understand the
risk benefit. It needs to be done under strict
oversight and it needs to be restricted to

English: 
>>> ANY OF THE ISSUES WE TALKED
ABOUT TODAY, WHO IS GIVING
CONSENT FOR THIS.
THE CHILD IS SOMEBODY WHO NEVER
GAVE CONSENT TO BEING
GENETICALLY EDITED.
AND THE RISK WE ARE GOING DOWN A
SLIPERY SLOPE, AND USING IT TO
ENGINEER EDITING FOR DISEASE,
WOULD THEY SOON DO THIS FOREIGN
HANSMENT.
>>> WHAT THE COMMITTEE CAME TO
THE CONCLUSION, IS THAT CAUTION
IS NEEDED, BUT CAUTION DOES NOT
MEAN PROHIBITS.
WE PROPOSE THAT HEARTH MANY
EDITING FOR TREATMENT OF SERIOUS
DISEASE MIGHT BE PERMANENTED --

English: 
PERMITTED BUT ONLY AFTER A
SERIOUS CRITERIA WERE MET.
NEED TO RESTRICT OVERSIGHT, OR
RESTRICTED TO A SPECIFIC SET OF
CRITERIA, WHICH IS LISTED OVER
HERE.
ONE REASONABLE ALTERNATIVE IS IN
VITRO EDITING.
FOR MANY COUPLES THAT'S A
POSSIBILITY.
WE KNOW IN THE U.S. THAT IS NOT
PAID FOR.
COUPLES NEED TO TAKE THE CHANCE.
THEY NEED TO, YOU KNOW, TAKE
THAT CHANCE.
>>> IN OTHER COUNTRIES, HOWEVER,
IVF IS PAID FOR.
THE GOVERNMENT PAYS FOR UP TO
TWO CHILDREN FOR, VF.
IF YOU WILL INITIATE A CLINICAL
TRIAL, YOU -- IT NEEDS TO IT BE
TO PREVENT A SERIOUS DISEASE OR
CONDITION.
IT HAS TO BE SOMETHING
IMPORTANT.
>>> ONE OF THE DISEASES I

English: 
a specific set of criteria which are listed
here.
The first is that there’s an absence of
reasonable alternatives. One reasonable alternative
of course is in vitro fertilization with preimplantation
genetic diagnosis and for many couples that
is a possibility. Now we know in the US that’s
not paid for. Couples need to take the chance.
They need to take that chance. In other countries,
however, IVF is paid for. In Israel for example
every couple the government pays for up to
2 children by IVF. If you’re going to initiate
a clinical trial, it needs to be to prevent
a serious disease or condition; that it has
to be something very important. One of those
diseases that I mentioned that probably couldn’t
be cured any other way. You need to change
the DNA sequence back to a sequence that we

English: 
know is healthy in humans. This is actually
an incredibly restrictive criterion because
we’re saying you can’t just change it
to what you think would be right, you have
to document that in the human population this
sequence has been shown to be healthy. That’s
actually more complicated than it sounds.
So that’s bullet point four. There has to
be, of course, available preclinical and clinical
data on the risks and benefits. There needs
to be ongoing rigorous oversight during the
clinical trials to make sure that the research
participants are healthy and safe and are
being ethically discussed with. There has
to be plans for long-term multigenerational
followup. There has to be maximum transparency
and continued reassessment of both health
and societal benefits and here’s an important
point, with broad ongoing participation and
input by the public. Not broad ongoing participation
by a few sets of scientists or a few sets
of this and that, but by the public in general.

English: 
MENTIONED, THAT PROBABLY
COULDN'T BE CURED ANY OTHER WAY.
YOU NEED TO CHANGE THE DNA
SEQUENCE BACK TO THE WAY WE KNOW
IS HEALTHY IN HUMANS.
THIS IS AN INCREDIBLY
RESTRICTIVE CRITERIA.
YOU HAVE TO DOCUMENT THAT IN THE
HUMAN POPULATION, THIS SEQUENCE
HAS SHOWN TO BE HEALTHY.
THAT'S ACTUALLY MORE COMPLICATED
THAN IT SOUNDS.
THAT'S BALL POINT NUMBER 4.
THERE HAS TO BE PRE-CLINICAL AND
CLINICAL DATA ON THE BENEFITS.
>>> ONGOING RIGOROUS OVERSIGHT,
TO MAKE SURE THE PARTICIPATES
ARE HEALTHY AND SAFE, AND BEING
ETHICALLY DISCUSSED WITH.
>>> PLANS FOR LONG-TERM MULTI
GENERATIONAL
FOLLOW-UP.
MAXIMUM TRANSPARENCY, AND HEALTH
AND SOCIETAL BENEFITS.
AND IMPORTANT

English: 
It can’t be behind closed doors. Then there
has to be reliable oversight mechanisms so
that the use doesn’t get applied to beyond
treating or preventing a serious condition.
What are the key messages then of the overall
report? Basic research and somatic gene therapy
is valuable and adequately regulated by current
mechanisms; that somatic therapy should be
used only for the treatment and prevention
of disease and disability, not for enhancement
at this time; that heritable genome editing
needs more research before it might be ready
to be tried; and more public input is needed
before it is considered. If and when it is
tried it must be approached cautiously and
only if it meets very strict criteria and
stringent oversight.
With that, I will end and I think we’ll

English: 
POINT, ONGOING
PAPERS BY THE CLIENT.
BUT BY THE PUBLIC IN GENERAL.
IT CAN'T BE BEHIND CLOSED DOORS.
AND OVERSIGHT MECHANISMS, SO
THAT THE USE DOESN'T GET APPLIED
BEYOND TREATING OR APPLYING A
SERIOUS CONDITION.
>>> SO, ONE OF THE KEY MESSAGES
OF THE OVERALL REPORT, BASIC
RESEARCH IN SOMATIC RESEARCH, IS
VALUABLE, AND SOMATIC SHALL ONLY
BE USED
FOR -- MORE PUBLIC INPUT
BEFORE IT IS CONSIDERED.
IF AND WHEN IT IS TRIED, IT MUST
BE APPLIED CAUTIOUSLY AND

English: 
STRINGENT OVERSIGHT.
WITH THAT, I WILL END AND I
THINK WE WILL GO TO THE Q&A
SESSION.
THANK YOU VERY MUCH.
[APPLAUSE]
>> The Moderator: I FORGOT TO
MENTION, THERE ARE CARDS IN YOUR
FOLDERS, IF YOU HAVE QUESTIONS,
PLEASE WRIGHT THEM DOWN, AND WE
HAVE A COUPLE EVENT STAFF, AND
PICKING THOSE UP.
SO, MAYBE WE SHOULD
START WITH A QUESTION,
WHILE WE ARE WAITING,
UNLESS SOMEONE HAS ONE
READY?
>>> ONE THING, AND I
DON'T KNOW IF THIS
PERTAINS, A LOT OF
INDIVIDUALS TALK ABOUT,
WE ARE SHORTAGE OF
ORGANS, COULD YOU TALK
ABOUT THAT WHILE WE ARE
WAITING FOR A QUESTION.
>> SURE, YEAH.
WE KNOW, MANY, MANY
PEOPLE ARE DYING BECAUSE

English: 
go to the Q&A session. Thank you very much.
Jean Nagelkirk:
Well one thing and I don’t know if this
totally pertains, but a lot of individuals
talk about a shortage of organs. Can you talk
a little bit about that while we’re waiting
for a question?
Dr. Porteus:
Sure. We know many, many people are dying
because they need a solid transplant or a
solid organ transplant and they’re not available.
There is, on paper, a potential solution to

English: 
THEY NEED A SOLID ORGAN
TRANSPLANT AND THEY ARE
NOT AVAILABLE.
THERE IS ON PAPER A
SOLUTION TO THIS.
WHICH, ONE OF THE --
WHICH IS TO USE GENOME
EDITING AS A WAY OF
ENGINEERING ORGANS, SO
THAT YOU HAVE MORE
MATCHES.
THAT'S PRETTY FAR DOWN
THE ROAD.
SO, YEAH, IN THERAPY.
I DON'T THINK IT IS A
NEAR TERM SOLUTION TO
THAT PROBLEM.
>> ANOTHER ONE, WHILE I
AM WAITING FOR OTHERS,
IS:  PEOPLE TALK ABOUT
PERSONALIZED MEDICINE.
>> YEAH.
>> I GET SOME FORM OF
CANCER AND I MAY REACT
BADLY TO
CHEMOTHERAPEUTIC AGENT,
BUT IF IF YOU COULD TEST
IT OUT SO I DON'T GET
SIDE EFFECTS.
WHERE IS THAT, AND WHERE
MIGHT WE BE LOOKING AT?
>> I DON'T THINK WE WILL

English: 
this which is to use genome editing as a way
of engineering organs so you have more matches.
But that’s pretty far down the road. In
theory, but I don’t think it’s a near-term
solution to that problem.
Jean Nagelkirk:
And another one while I’m waiting for others,
people talk about personalized medicine often.
I get some form of cancer and I may react
badly to some chemotherapeutic agent but if
you could test it out before I get it so I
don’t have all those bad side effects, where
is that and what might we be looking at?
Dr. Porteus:
Again, I don’t think we’d be able to say
edit you to make you so that you have less
side effects. But I think that genome editing
does intersect with the world of personalized

English: 
SAY EDITING YOU, BUT IT
DOES INTERSECT IN MANY
WAYS.
ONE IS OF COURSE, NOT
CANCER, PER SE, SAY YOU
HAVE A GENETIC DISEASE,
IF WE CAN GO IN, AND
CORRECT THAT VARIANT
THAT IS CAUSING YOU TO
HAVE THE DISEASE, THAT
IS HIGHLY PERSONALIZED
MEDICINE.
>>> I THINK THE OTHER
ONE SO GENOME EDITING,
WE KNOW, FOR EXAMPLE,
THAT EACH CANCER HAS AND
GENERALS, THAT COULD
MAKE THAT CANCER
SUSTAINABLE ACCEPTABLE
TO AN IMMUNE SYSTEM
ATTACK.
GENOME EDITING IS LIKELY
TO PLAY A ROLE IN TERMS
OF
LIMB -- ELIMINATE
CANCER, TO KILL THAT
CANCER.
>> GOOD, WE HAVE ONE
QUESTION.
GO AHEAD.
>> MY PERSPECTIVE ON
THOSE SORT OF QUESTIONS
ON PERSONALIZED
MEDICINE.

English: 
medicine in many ways. One is of course if
you have, not cancer per se, but say you have
a genetic disease, if we can go in and correct
that variant that’s causing you to have
the disease, that is highly personalized medicine.
I think the other application of genome editing
to cancer therapeutics is that we know for
example that each cancer has antigens that
could make that cancer susceptible to immune
system attack. I think genome editing is likely
to play a role in enhancing our immune system
in terms of eliminating cancers. Probably
not editing of the cancer itself, editing
of the immune system to enhance its activity
to potentiate its activity in killing that
cancer.
Dr. MacKeigan:
My perspective on questions of personalized
medicine. The definition of personalized medicine
is evolving as the years go by and I think
we’re going to look back and see something
like genome editing of your own immune cells

English: 
I THINK THE DEFINITION
IS EVOLVING AS THE YEARS
GO BY.
I THINK WE WILL LOOK
BACK AND SEE GENOME
EDITING OF YOUR OWN
IMMUNE CELLS, TO
SEQUENCING YOUR OWN DNA
TO MATCH THAT.
>>> I THINK IT WILL BE A
FORM OF PERSONALIZED
MEDICINE.
>>> MY PERSPECTIVE ALSO,
AS AN UNDERGRAD, I
WORKED FOR A GENE
COMPANY THERAPY, IN A
COMPANY OUT OF SAN
FRANCISCO, OUT OF
COLLEGE, SO THE
REGULATORY PIECES IN
PLACE, AND BACK TO YOUR
ORGAN QUESTION, OR
GRAVITYING QUESTION OF
NEW ORGANS, TARGETING IS
DIFFICULT AND HAS BEEN
FOR ALL OF THESE.
I THINK THE PROMISE
BEING IN EXAMINE RECEIVE

English: 
to be a form of personalized medicine versus
just sequencing your tumor DNA right now and
trying to match a therapy to that. I do think
that it will be a form of personalized medicine
or customized T cells if you will that are
put back into the body to attack those. My
perspective also is out of undergrad I worked
for a gene therapy company in San Francisco
as my first job out of college. That was sort
of mentioned earlier, the regulatory pieces
that are in place have been around for certainly
____ years with gene therapy and back to your
organ question or grafting question of new
organs, targeting is very difficult and it
has been for all these and so I really see
the promise being in the area of ex vivo delivery
because safe and effective and complete delivery
to even a solid organ would be very difficult
obviously.
Jean Nagelkirk:

English: 
You mention improving specificity. How specific
does CRISPR need to be before going to clinical
trial?
Dr. Porteus:
Well, I think the current versions are specific
enough. I think what we’ve learned…so
one of the other aspects of my research group
is to try to actually engineer cancer in human
cells and then put it into a mouse. It’s
really difficult to do. So, what we’ve shown
is that when we engineer our human cells and
we put them into mice we never see any evidence
of a cell gone awry. And so I think what that
means is that we’ll never be able to prove
it’s absolutely safe using mouse models
and instead I think the biochemistry and our
analysis of where the off-target breaks suggest
for serious diseases that it is now worth

English: 
VOW EDITING.
>>> IT IS REALLY
DIFFICULT TO DO.
WHAT WE HAVE SHOWN, WHEN
WE ENGINEER, OUR HOW
MANY CELLS, AND PUT THEM
INTO A MICE, WE NEVER
SEE EVIDENCE OF OF A
CELL GONE AWRY.
>>> INSTEAD, THE BIO
CHEMISTRY AND ANALYSIS

English: 
trying this in patients who have a serious
disease in which they have no other, there’s
an unmet medical need. And then we have to
follow those patients. If it turns out to
be safe there, then you start expanding the
list of diseases. This is why again we don’t
want to be using genome editing for things
that aren’t serious at this point because
we’re only going to understand the true
risks when we try this in patients.
Dr. MacKeigan:
As a research tool, we use human cancer lines
and we’ll modify those drivers of cancer
called oncogenes and we’ll modify the tumor
suppressors with CRISPR/Cas technology simply
as a basic research tool to make one scientific
change or genetic change to those cells and
then they’re paired and then we can start
to work down very basic questions on how those
cancer cells respond to different therapies.
My feeling, and it was discussed earlier in
the afternoon session, is that the old approaches

English: 
OF WHERE THE OFF TARGET
BREAKS SUGGESTS FOR
SERIOUS DECEASES, THAT
IT IS NOW WORTH TRYING
INPATIENTS WHO HAVE A
SERIOUS DISEASE, AND
THERE IS THAT MEDICAL
NEED.
>>> AND WE HAVE TO
FOLLOW THOSE PATIENTS.
IF IT TURNS OUT TO BE
SAFE THERE, THEN YOU
START LISTING THE
DISEASES.
>>> THIS IS WHY, AGAIN,
WE DON'T WANT TO USE
GENOME EDITING FOR
THINGS NOT SERIOUS AT
THIS POINT.
WE WILL ONLY UNDERSTAND
THE TRUE RISKS WHEN WE
TRY THIS ON PATIENTS.
>> THIS IS A RESEARCH
TOOL.
WE WOULD USE HUMAN
CANCER CELL LINES, AND
WE WILL MODIFY THE
DRIVERS OF CANCER, CALL
ORANGE GENES, AND MODIFY
THE TUMOR REPRESS SO
AVES WITH TECHNOLOGY AS
A RESEARCH TOOL, TO MAKE
A GENETIC CHANGE TO THE
CELLS AND THEY ARE

English: 
of viral integration were certainly multiple
copies upwards of 9 or even hundreds of copies
of viral inserts were being placed at total
random and you couldn’t predict this. As
was mentioned earlier that we can predict
the insertion spots probably pretty effectively
and just daily living, given as a perfect
example, flying here was more dangerous than
probably doing a CRISPR/Cas9 experiment.
Jean Nagelkirk:
How would you compare/contrast genome editing
for enhancement versus cosmetic surgery for
enhancement?
Dr. Porteus:
Right to it, you guys. That is sort of the
sticky wicket that everyone is struggling
with. What is fundamentally different about
somebody having a surgical procedure for a
cosmetic trait versus using a genetic tool
for enhancement? Is there something ethically

English: 
PAIRED, AB THEN WE CAN
WORK DOWN TO BASIC
QUESTIONS HOW THEY
RESPOND TO DIFFERENT
THERAPIES.
>>> MY FEELING WAS
EARLIER SESSION, THE OLD
APPROACHES OF VIRAL
INTEGRATION WAS MULTIPLE
COPIES, UP TO 9 OR
HUNDREDS OF COPIES OF
VIRAL INCERTIFICATES
WERE PLACED AT TOTAL
RANDOM AND YOU COULDN'T
PREDICT THIS.
AS TOLD EARLIER, WE
COULD PROBABLY -- FLYING
HERE WAS MORE DANGEROUS
THAN DOING A CASINO 9
EXPERIMENT.
>> HOW WOULD YOU COMPARE
CONTRAST, DO YOU EDITING
FOREIGN HANSMENT, VERSUS
COSMETIC ENHANCEMENT.
>> RIGHT TO IT, YOU
GUYS.
[LAUGHTER]
>> THAT IS SORT OF THE
STICKY WICKET.
WHAT IS FUNDAMENTALLY
ABOUT SOMEBODY HAVING A
SURGICAL PROCEDURE FOR

English: 
COSMETIC TRAIT, VERSUS
USING A GENETIC TOOL
FOREIGN HANSMENT?
IS THERE SOMETHING
ETHICALLY DIFFERENT
BETWEEN THOSE THINGS?
>>> I DON'T LIKE THE
ANSWER, TO ME, THERE IS
AN ICK FACTOR, BUT I
CAN'T PUT MY FINGER ON
IT.
ALMOST EVERY SURGICAL
PROCEDURE FOREIGN
HANSMENT IS REVERSIBLE.
RIGHT NOW, IF YOU DID
GENOME EDITING OF CELLS,
WE WOULDN'T KNOW HOW TO
REVERSE THAT.
SO, PERHAPS, IT IS THE
REVERSIBILITY THAT
ALLOWS YOU TO
DISTINGUISH THE TWO.
BUT, IT IS THE ONE THAT
PEOPLE BRING UP.
LIKE, IF YOU ALLOW
ENHANCEMENT HERE, WHY
WOULDN'T YOU ALLOW
ENHANCEMENT THERE?
I WISH ALTA WAS HERE.
SHE WOULD HAVE A BETTER
ANSWER.
>>> I WOULD BE

English: 
different between those things? I don’t
like this answer, but to me there’s an ick
factor that’s different, but I can’t put
my finger on it. What maybe is more concrete
is that almost every surgical procedure for
enhancement is reversible. And right now if
you did genome editing of cells, we really
wouldn’t know how to reverse that quite
easily. One could imagine some reversible
systems so perhaps it’s the reversibility
that allows you to distinguish the two. But
it is the one that people bring up like well
if you allow enhancement here, why wouldn’t
you allow enhancement there? I wish Alta was
here, she’d have a better answer. I would
be interested if anyone else has what in their
mind distinguishes...
Audience:

English: 
INTERESTED IF ANYONE
--
[INDISCERNIBLE]
>> The Moderator: CAN YOU SAY
YOUR NAME, PLEASE?
>> I AM JEFF BURNS.
THE QUESTION WAS ABOUT
COSMETIC?
>> WHY DO WE DO MILLIONS
OF COSMETIC SURGERIES
FOREIGN HANSMENT IN THE
U.S., AND YET WE WOULD
SAY, AGAIN TICK
ENHANCEMENT USING GENOME
EDITING WOULD NOT BE
ALLOWED?
>> I WONDER IF THAT WAS
THE QUESTION.
I THINK I HEARD THE
QUESTION SLIGHTLY
DIFFERENTLY.
WHICH WAS, IF WE DO
GENETIC ENHANCEMENT, WHY
WOULDN'T WE ALLOW
GENETIC ENHANCEMENT.
THERE IS A SUBSTANTIAL
DIFFERENCE DRIVING
PEOPLE TOWARD HEALTH
INSTEAD OF HAPPY TO BE
SOCIALLY

English: 
I’m Jeff Burns. The question was about cosmetic...
Dr. Porteus:
Why do we do millions of cosmetic surgeries
for enhancement in the US and yet we would
say genetic enhancement using genome editing
should not be allowed?
Jeff Burns:
I wonder if that was the question. I think
I probably heard the question slightly differently
which is if we do genetic enhancement why
wouldn’t we allow genetic enhancement for
cosmetic reasons? It seems to me that there
is a substantial difference in the value there
driving people toward health versus driving
people toward appearing in the way that they
want or appearing in the way that seems more
socially acceptable. There seems to be a substantial
difference in how we value those two different
parts. At least we’d want to mark a distinction
like that.
Jean Nagelkirk:
The next question, isn’t it a worry that

English: 
my editing treatment could overcorrect my
problem? In other words, do we know what the
correct DNA should be?
Dr. Porteus:
For many diseases we do. So, for example,
for sickle cell disease, I know the nucleotide
sequence that is hemoglobin A, we know that
that’s fine, and we know the nucleotide
sequence for hemoglobin S, which isn’t fine,
and if I convert the S sequence to the A sequence
we know it’s fine. I think for many, many
genetic diseases that is sort of the appeal
of genome editing, is you can revert a disease-causing
sequence to a known sequence that doesn’t
cause disease. Now, people are thinking about
using genome editing to engineer cells, to
secrete more of an enzyme to correct an underlying
enzyme defect or gene therapies being used
to treat hemophilia which is a disease where
people don’t make enough clotting factor.

English: 
ACCEPTABLE.
>> The Moderator: THE NEXT
QUESTION:  ISN'T IT A WORRY THAT
MY EDITING TREATMENT COULD OVER
CORRECT MY PROBLEM?
IN OTHER WORDS, DO WE
KNOW WHAT THE CORRECT
DNA SHOULD BE?
>> FOR MANY DISEASES, WE
DO.
FOR SICKLE-CELL DISEASE
I KNOW THE SEQUENCE THAT
IS HEMOGLOBIN A, AND IF
I CONVERT THE S SEQUENCE
TO THE A SEQUENCE, WE
KNOW IT IS FINE.
>>> I THINK FOR MANY,
MANY GENETIC DISEASES,
THAT'S THE SORT OF THE
APPEAL OF GENOME
EDITING, YOU CAN REVERT
A DISEASE CAUSING
SEQUENCE TO A KNOWN
SEQUENCE THAT DOESN'T
CAUSE DISEASE.

English: 
>>> LIKE HEEL FEEL I
CAN'T, WHERE PEOPLE
DON'T MAKE ENOUGH OF A
CLOTTING FACTOR.
WOULD IT BE DANGEROUS TO
GET TO 2 100%?
THAT ACTUALLY, THAT
RANGE OF SAFE, THAT
THERAPEUTIC RANGE OF HE
HAVE IF A KA SEE AND
SAFETY, I THINK, HAS TO
COME FROM HUMAN
GENETICS.
WE KNOW PEOPLE OUT THERE
DON'T HAVE A PROBLEM
WITH 150% LEVEL,
THEREFORE THAT GIVES UP
AN UPPER LIMIT OF
NORMAL.
>> I GUESS TWO OTHER
EXAMPLES OF THAT.
CERTAINLY WITH A DISEASE
DISEASE, TUBE BORE
SCLEROSIS, WHERE
CHILDREN ARE BORN WITH A
DEFECTIVE GENE, TSC1 OR
2, AND SOMEWHAT HOPEFUL
FOR THE FAMILIES TO GO

English: 
We know we need to get to 10% level to have
an effect. Would it be dangerous to get to
200%? That range of safe, that therapeutic
range of efficacy and safety, I think has
to come from human genetics where we know
there are people out there who don’t have
a problem with 150% level and so therefore
that gives us an upper limit of normal.
Dr. MacKeigan:
Two other examples of that. Certainly with
a disease I studied called tuberous sclerosis
complex where children are born. It’s not
that rare of a disease about 1 in 6000 incidents.
They’re born with a defective gene in either
the gene called TSE1 or TSE2. It is somewhat
hopeful for those families to think that you
could go in and repair that gene and they
wouldn’t have multisystem tumor syndrome
or neurologic complications such as daily
seizures. With the same example there, we

English: 
know the normal sequence. There is some variation
but it still drives the normal sequence of
the normal protein and its normal function.
So I guess, on that second case of an example
of we know the sequence and we could repair
it.
Dr. Porteus:
Do you get the level right?
Dr. MacKeigan:
I was thinking of an example from Parkinson’s
disease. The PARK1 gene or the PARK1 loci
encodes a gene called the synuclein
and some recent studies not too long ago,
about 15 years ago, showed the just gene dosage,
so 5 extra copies of that gene, is more than
enough to drive disease symptoms and even
disease in animals and in patients. So even
animal models that we use in the laboratory
to study Parkinson’s disease, we’ll put
in multiple copies of the wild-type normal
gene. Some people use other sophisticated
techniques where we put in misfolded proteins,
highlighting that 5 extra copies is enough
to drive a disease in that situation.

English: 
IN THERE AND REPAIR THE
GENE, AND THEY WOULD NOT
HAVE A MULTI TUMOR
SYNDROME OR SEIZURES.
>>> WE KNOW THE NORMAL
SEQUENCE, THERE IS SOME
VARIATION, BUT DRIVES
THE -- I GUESS ON THAT
SECOND CASE OF AN
EXAMPLE, WE KNOW THE
SEQUENCE, AND WE COULD
REPAIR IT.
THE OTHER COMMENT -- I
HAVE LOST MY TRAIN OF
THOUGHT ON THE SECOND
ONE.
>> YOU JUST ABOUT GET
THE LEVEL RIGHT.
>>  I WAS THINKING OF A
PARKINSON'S, AND THERE
IS A GENE, IN SOME
RECENT STUDIES, ABOUT 15
YEARS AGO, SHOWN GENE
DOSES, IT IS MORE THAN
ENOUGH TO DRIVE DISEASE
SYMPTOMS, IN ANIMALS AND
PATIENTS.
EVEN ANIMAL MODELS WE

English: 
Dr. Porteus:
So that leads to the level we want to achieve
can be also studied in animal models, recognizing
that a mouse is not a human and the limitations.
Jean Nagelkirk:
How do we define the limits of disease and
disability? For example, is it ethical to
use this technology to treat disabilities
like Down syndrome? Is there a mechanism in
place for advocating what constitutes disease
and what should be left alone as diversity?
Dr. Porteus:
Yeah, you guys are spot on. These are all
exactly the hard questions that the committee
wrestled with over and over again. If you
look at the report there are gaps in the committee
report because we didn’t have great answers.
Here are some ideas around that idea. Down
syndrome is an interesting one. The example
that comes up a lot is the issue of congenital

English: 
USE TO STUDY, AND SOME
PEOPLE USE OTHER
TECHNIQUES PUTTING IN
PROTEINS.
>>  SO, THAT LEADS TO
THE LEVEL WE WANT TO
ACHIEVE, CAN BE ALSO
STUDIED IN ANIMAL
MODELS, RECOGNIZING A
MOUSE IS NOT A HUMAN AND
THE LIMITATIONS.
>> The Moderator: OKAY, HOW DO
WE DEFINE THE LIMITS OF OF
DISEASE?
IS IT ETHICAL TO TREAT
DISABILITIES LIKE DOWN
SYNDROME?
IS THERE A MECHANISM IN
PLACE FOR ADVOCATING
WHAT CONSTITUTES DISEASE
AND WHAT SHOULD BE LEFT
ALONE AS DIVERSITY?
>> YOU GUYS ARE SPOT ON.
THESE ARE EXACTLY THE
HARD QUESTIONS THAT THE
COMMITTEE WRESTLED WITH
OVER AND OVER AGAIN.
>>> IF IF YOU LOOK AT
THE REPORT, THERE ARE
GAPS IN THE COMMITTEE
REPORT, BECAUSE WE
DIDN'T HAVE GREAT
ANSWERS.
>>> HERE ARE SOME IDEAS
AROUND THAT HAD WHY.
DOWN SYNDROME IS AN

English: 
INTERESTING ONE.
THE EXAMPLE THAT COMES
UP A LOT IS THE ISSUE OF
CONGENITAL DEAFNESS.
SOME PEOPLE WHO HAVE
CONGENITAL DEAFNESS, HO
SEE THEIR TRAIT AS A
DISEASE, AND WOULD MAKE
SURE HAVE KIDS WHO
DIDN'T HAVE THAT.
>>> THERE ARE OTHER
PEOPLE WHO SEE PEOPLE
WITH CONGENITAL DEAFNESS
AS A RANGE OF NORMAL,
AND THIS IS A SPECTRUM
OF HUMAN NORMALNESS AND
MAINTAIN IT.
>>> IN FACT, THERE ARE
ANECDOTES OF OF PARENTS
INTENTIONALLY HAVING
KIDS WHO WILL HAVE DEAF
TO MAINTAIN THE
DIVERSITY.
I DON'T THINK IT IS UP
TO US, TO TELL A
COMMUNITY OR ANY PARENT
WHAT THEY SHOULD OR
SHOULD NOT DO.
>>> IF WE MADE IT AS IF,
IF YOU DIDN'T USE THIS
TECHNOLOGY, YOU ARE
SOMEHOW A LESS PARENT
THAT WOULD BE WRONG.
>>> ON THE OTHER HAND, I

English: 
deafness where there are some people who have
congenital deafness who see their trait as
a disease and they would make sure to have
kids that didn’t have congenital deafness.
There are other people who see people with
congenital deafness who see congenital deafness
as a range of normal and that this is just
a spectrum of human normalness and we should
maintain it. In fact there are sort of these
anecdotes of parents intentionally having
kids who will be deaf to maintain that diversity.
I don’t think it is up to us to tell any
community or any parent what they should or
shouldn’t do. I think one of the concerns
is if we made it as if you didn’t use this
technology you were somehow a less parent
that would be wrong. On the other hand, I
think for serious diseases we can develop
the therapies and allow families and people
to make the choice for themselves about whether

English: 
THINK FOR SERIOUS
DISEASES, WE CAN DEVELOP
THE THERAPIES, AND I --
AALLOW FAMILIES TO MAKE
THE CHOICES THEMSELVES.
>>> HOW DO WE DEFINE
WHETHER SOMETHING IS A
DISEASE, DISABILITY OR
TRAIT?
WE WERE TALKING THIS
AFTERNOON ABOUT LIVING
IN THE WORLD OF GRAY,
THAT'S A HUGE WORLD OF
GRAY.
CERTAINLY I DON'T WANT
TO BE THE ONE DEFINING
IT, AND I DON'T THINK I
WANT AN EXPERT COMMITTEE
DEFINING IT.
THAT'S A COMPLICATED
ISSUE.
I ASK JEFF AND HOW YOU
GUYS DEFINE IT?
>> MORE PUBLIC INPUT ON
THIS, I GUESS,
PRE-DESCRIBING THOSE
CONDITIONS, WHEN TO
TREAT AND NOT TO TREAT,
I DON'T KNOW IF THERE
ARE MANY IN THE AUDIENCE
THAT WOULD AGREE WITH
THAT.
>> The Moderator: OKAY.
PLEASE SPEAK TO THE
ROLE, I THINK IT SAYS,
U.S.A. HEALTH CARE, KS

English: 
they choose to use it or not. How do we define
whether something is a disease or a disability
or a trait? I mean, we were talking this afternoon
about living in the world of grey. That’s
a huge world of grey and certainly I don’t
want to be the one defining it and I don’t
think I want an expert committee defining
that. I think that’s a complicated issue,
I don’t know. Again, I’d ask Jeff and
I’d ask you guys how you’d define that.
Dr. MacKeigan:
More public input, I guess on this is that
predescribing those conditions and when to
treat and not to treat, I don’t know if
there are many in the audience that would
agree with that.
Jean Nagelkirk:
Okay. Please speak to the role of USA Healthcare
chaos? funding with genomic editing.
Dr. Porteus:

English: 
Okay, that’s a great question because I’m
going to answer it any way 
I want. A few months ago I had the opportunity
to testify in front of the Senate HELP Committee.
Lamar Alexander and Patty Murray chair that
committee and they were very interested in
the technology of genome editing and they
were very nice. They treated us, the three
panelists, quite respectfully. They were highly
interested in what we were doing and they
had words of praise. So that was great and
this is a new technology. At the same time
they were having that committee meeting, the
renewal of CHIP, the Children’s Health research
funding for children who didn’t have health
research, hadn’t been reauthorized. Now
it’s been since reauthorized. I agree that
there is a little disconnect here between
being excited about future technologies without
providing the funding and insurance mechanisms

English: 
SPENDING WITH GENOMIC
EDITING?
>> THAT'S A GREAT
QUESTION, I WILL ANSWER
IT ANYWAY I WANT.
SO, UM, A FEW MONTH
AGO, -- SO -- LET ME
GO -- A FEW MONTH AGO, I
HAD THE OPPORTUNITY TO
TESTIFY, THEY WERE VERY
INTERESTED IN THE
TECHNOLOGY OF OF GENOME
EDITING.
THEY ARE NICE, AND
TREATED US THE THREE
PANELISTS QUITE
RESPECTFULLY, THEY HAD
WORDS OF PRAISE.
>>> THAT WAS GREAT.
THIS IS A NEW
TECHNOLOGY.
AT THE SAME TIME, THEY
WERE HAVING THAT
COMMITTEE MEETING, THE

English: 
to take care of people today. And that we
should all be fighting with for in our own
time. Hopefully I answered the question that
the person tried to ask. There is a disconnect
here.
Dr. MacKeigan:
What’s the projected cost for repairing
sickle cell disease? Maybe just shock us a
little bit.
Dr. Porteus:
There’s what, let’s see, I think there
are 3 gene therapy drugs that have been commercially
approved one in Europe, two in the US, and
the cost for a single dose of the therapy
is ranging between $300,000 and $800,000.
That’s not including all the ancillary costs
of taking care of the patients. That’s just
for the drug itself. Now for sickle cell disease
or hemophilia where the lifetime cost might
approach $10-$20 million dollars, one could

English: 
RENEWAL OF CHIP WASN'T
AUTHORIZED BUT HAS SINCE
BEEN AUTHORIZED.
THEY WERE EXCITED ABOUT
FUTURE TECHNOLOGIES, AND
FUNDING TO TAKE CARE OF
PEOPLE TODAY.
THAT IS ALL WHAT WE
SHOULD BE FIGHTING FOR
IN TIME.
HOPEFULLY I ANSWERED THE
QUESTION.
>> WHAT IS THE PROJECTED
COST FOR REPAIRING
SICKLE-CELL DISEASE AND
MAYBE JUST --
>> YEAH, SO, THERE IS,
WHAT, LET'S SEE, THERE
ARE THREE GENE THERAPY
DRUGS THAT HAVE BEEN
COMMERCIALLY APPROVED,
ONE IN EUROPE, TWO IN
THE U.S.
A COST FOR A SINGLE DOSE
OF THE THERAPY IS
RANGING BETWEEN
$300,000, AND $800,000.
THAT'S NOT INCLUDING OF
ANCILLARY COSTS OF
TAKING CARE OF THE
PATIENT.
THAT'S FOR THE DRUG
ITSELF.
SOME OF THOSE COSTS, --

English: 
NOW FOR SICKLE-CELL
DISEASE OR HEEL FEEL I
CAN'T, WHERE THE
LIFETIME COST MIGHT
REACH 10 TO $20 MILLION,
IF ONE SHOT KILLED IT IN
ONE SHOT IT IS
EFFECTIVE.
>>> SO, YEAH.
>> The Moderator: OKAY.
DR. PORTEUS, IN YOUR
INTERACTIONS WITH
PATIENTS OF SICKLE-CELL
DISEASE, HAVE THEIR
SHARED THEIR THOUGHTS ON
THE POTENTIAL OF GENOME
EDITING?
>>  SO, I HAVE HAD -- I
HAVE BEEN ABLE TO TALK
TO FAMILIES IN THE AREA
ABOUT GENOME EDITING.
BUT I DON'T THINK THAT'S
A REPRESENTATIVE
COMMUNITY OF OF
SICKLE-CELL PATIENTS.
CLEARLY, I AM GETTING A
BIAS SAMPLE.
THEY ARE EXCITED, AND
OFTEN ADMIT THEY DON'T
KNOW A LOT.
BUT IT IS A COMMUNITY
WHERE SOME OF LEADERS IN
THE CELL -- THEY OKAY
KNOWLEDGE THAT THE
COMMUNITY IS
UNDERGRADUATED.

English: 
say a one-shot curative therapy at $500,000
is cost effective. But for other diseases
that calculus is less well established, so
yeah.
Jean Nagelkirk:
Dr. Porteus in your interactions with patient
with sickle cell disease, have they shared
their thoughts on the potential of gene editing?
Dr. Porteus:
So I’ve been able to talk to families in
the Palo Alta area about genome editing, but
I don’t think that that’s a representative
community of sickle cell patients. Clearly
I’m getting a biased sample. They’re very
interested. They’re excited. They often
admit that they don’t know a lot, but it
is also a community where I’ve interacted
with some of the leaders of the sickle cell
communities and they admit that their community,
well I wouldn’t say admit, they acknowledge
that the community is undereducated. One of
my new year’s resolutions for 2018 is to

English: 
ONE OF, I THINK, MY NEW
YEAR'S RESOLUTIONS FOR
2018 TO BECOME MORE
ACTIVELY ENGAGED IN THE
COMMUNITIES, TO MAKE
SURE WE ARE WORKING HARD
IN THE LAB AND MAKE SURE
WE EDUCATE THE COMMUNITY
DIRECTLY AND LISTEN TO
THEM.
>> The Moderator: THE NEXT ONE,
WHAT ARE THE SOLUTIONS TO USING
CRISPER CAST 9, HOW CAN YOU TELL
WHO HAS THE ANTIBODIES, AND
WOULD THE OTHER CAST NUKE LEOUSS
WOULD ACCOMPLISH THIS?
>> WE ARE NOT A REALLY
SOPHISTICATED IMMUNOLOGY
LAB, AND WE COULD DO IT.
>>> WHAT ARE SOME OF THE
SOLUTIONS.
I THINK THE PERSON WHO
WROTE THE QUESTION, WAS
TO DEVELOP CAST 9 FROM
BACTERIA THAT DON'T
INFECT HUMANS.

English: 
become more actively engaged in those communities
and make sure that not only are we working
hard in the lab to develop this but also making
sure to engage the community and educate the
community directly and listen to them.
Jean Nagelkirk:
What are the solutions to using CRISPR/Cas9
in individuals who already have antibodies
to Cas9? How can you tell who has the antibodies
and will the use of other Cas nuclei prevent
this issue?
Dr. Porteus:
I think detecting whether somebody has preexisting
immunity is pretty simple. We’re not a really
sophisticated immunology lab and we can do
it, so I think that that will be pretty easy
to do with a blood spot test. So what are
some of the solutions? The person who wrote
the question implied probably the most likely
one which is to develop Cas9 systems from
bacteria that don’t infect humans. We know
these Cas systems exist in millions of different

English: 
bacteria so it’s just a matter of people
now going into that, going into that and developing
some system from bacteria that don’t infect
us. Another intermediate solution because
the Staph aureus and Strep pyogenes Cas9s
are so well developed, is our study just looked
at adults and it’s possible that for example
young children or infants haven’t yet developed
immunity to Cas9 and therefore there would
be a window of opportunity in terms of using
in vivo genome editing before they developed
that immunity. For many serious genetic diseases
that infect infants that’s still a path
forward so I think we need to understand when
in life this immunity develops.
Dr. MacKeigan:
Question for you – do you have any autoantibodies
against when you do it ex vivo? So obviously
you’re implying a lot of this was an application
that might be a little farther away in vivo.
But what about the ex vivo reactions?
Dr. Porteus:

English: 
WE KNOW THAT CAST
SYSTEMS EXIST IN
MILLIONS OF DIFFERENT
BACTERIA.
IT IS JUST A MATTER OF
PEOPLE GOING INTO THAT
.
>>> BECAUSE OF THESE
VIRUSES ARE SO WELL
DEVELOPED, OUR STUDY
JUST LOOKED AT ADULTS.
IT IS POSSIBLE, FOR
EXAMPLE, YOUNG CHILDREN
AND INFANTS HAVEN'T YET
DEVELOPED AN IMMUNITY TO
CAST 9 AND THERE WOULD
BE A REASON TO USE
GENOME EDITING.
FOR MANY DISEASES THAT
AFFECT INFANTS, THAT'S
STILL ON FAST FORWARD.
>>> WE NEED TO
UNDERSTAND WHEN IN LIFE
THIS IMMUNITY DEVELOPS.
>> DO YOU HAVE ANY
ANTIBODIES, WHEN YOU DO
AN EXAMINE RECEIVE VOW,
YOU ARE IMPLYING A LOT

English: 
By the time we give the cells back, the Cas9
is gone. So we don’t think it will be a
problem for ex vivo but we’ll see.
Dr. MacKeigan:
It’s degraded.
Dr. Porteus:
It’s degraded, that’s right.
Jean Nagelkirk:
Enhancement therapy is used, for example growth
hormone for short stature. Do any of the criteria
used for this apply to other enhancements?
Dr. Porteus:
Yeah, so short stature is another great question.
Is that a disease or a trait or a disability?
Now clearly parents feel like they want medical
therapy and so they get growth hormone for
that. There are pediatric endocrinologists
in the room. What is short? It’s a very
complicated question. The other thing, as
I’m talking about this, the use of growth
hormone is the prime example about repurposing
a drug. So it gets approved for one _____
and it gets used for another. The FDA actually
has put restrictions on the ability of physicians

English: 
OF THIS WAS APPLICATION,
WHAT BE THE X RECEIVE
VOW.
>> BY THE TIME WE GIVE
THE CAST BACK, THE
IMPLICATION IS GONE.
>> IT IS DEGRADED OVER
TIME.
>> THAT'S RIGHT.
>> The Moderator: GROWTH HORMONE
FOR SHORT STATURE, DO ANY OF THE
CRITERIA USED FOR THIS APPLY TO
ANY OTHER ENHANCEMENTS?
>> SHORT STATURE IS
ANOTHER GREAT QUESTION,
IS IT A DISEASE, TRAITOR
DISABILITY?
>>> PARENTS FEEL LIKE
THEY WANT MEDICAL
THERAPY, SO THEY GET A
GROWTH HOAR MOAN FOR
THAT.
HOW THEIR PEDIATRIC
CHRISTIANOLOGISTS IN THE
ROOM, WHAT IS SHORT?
IT IS A COMPLICATED
QUESTION.
AS I AM TALKING ABOUT

English: 
THIS, THE USE OF A
GROWTH HOAR MOAN, IS THE
PRIME EXAMPLE OF
REPURPOSING A DRUG.
IT GETS USED FOR ONE AND
THEN GETS USED FOR
ANOTHER.
>>> YOU CAN'T PRESCRIBE
GROWTH HOAR MOAN UNLESS
YOU HAVE REGISTERED WITH
THE FDA.
BUT THEY DON'T LIKE THAT
AT ALL.
>> The Moderator: I WILL GIVE
ANOTHER ONE, THEN.
WHAT ARE CURRENT
PROJECTED COSTS TO
PATIENTS, SUCH AS ONE
WITH SICKLE-CELL, SO
PROVEN THERAPY.
I THINK THIS WAS
ANSWERED, ANY COVERED,
INSURANCE OR
EXPERIMENTAL, I THINK
WAS THE OTHER PIECE OF
IT, COVERED IN A TRIAL,
OR SOMETHING?
>> THE GENERAL ISSUE IS
HOW DO PATIENTS WHO ARE
ENROLLED ON A NEW
CLINICAL TRIAL, HOW IS

English: 
to prescribe growth hormone. You can’t prescribe
growth hormone unless you have registered
with the FDA to prescribe growth hormone.
But they don’t like that at all. They do
not feel like that’s an effective system
to prevent the broad use of growth hormone.
I just said a lot without answering the question
because I don’t think I have a good answer.
Jean Nagelkirk:
I’ll give another one then. What are current
projected costs to patients such as one with
sickle cell to proven therapy? I think this
was answered. Any current coverage by insurances
or private pay for experimental, I think was
the other piece of it. Covered in a trial
or something.
Dr. Porteus:
Yeah, the general issue is how do patients
who are enrolled on a new clinical trial,
how is that paid for? Standard of care costs

English: 
will be paid for by insurance. The experimental
therapy then has to be paid for by someone
and that’s sometimes a really challenging
issue is who is going to pay for that? Hospitals
don’t like to cover that. So that’s why
you often are partnering with biotech or pharma
so that they pay for the clinical costs of
the drug, or you can get philanthropy to cover
it. But yeah, so usually in these clinical
trials the cost of coverage is a mixture between
insurance because you’re getting standard
of care therapies. For example, sickle cell
disease patients need blood counts periodically
so we’re not going to have to pay for those
blood counts but we’ll have to somehow pay
for the drug product. So it’s a hybrid.
Dr. MacKeigan:
The clinical development of any drug or biologic
in this instance needs a commercialization
path so to have a clear commercialization

English: 
THAT PAID FOR?
SO, IF IF THEY ARE
ELIGIBLE FOR A -- SO,
STANDARD OF CARE COSTS
WILL BE PAID FOR BY
INSURANCE.
THE EXPERIMENTAL THERAPY
HAS TO BE PAID FOR BY
SOMEONE.
THAT'S SOMETIMES A
CHALLENGING ISSUE, WHO
WILL PAY FOR IT.
HOSPITALS DON'T LIKE TO
COVER THAT.
THAT'S WHY YOU ARE OFTEN
PARTNERING WITH BIO TECH
OR FARM MA, SO THEY PAY
FOR THE TEST OF THE
DRUG.
>>> YEAH, USUALLY IN
THESE CLINICAL TRIALS,
THE COST OF COVERAGE IS
A MIXTURE OF INSURANCE,
YOU ARE GIVING STANDARD
OF CARE THERAPIES, FOR
EXAMPLE SICKLE-CELL
NEEDS BLOOD COUNTS, FOR
EXAMPLE.
WE DON'T HAVE TO PAY FOR
THE BLOOD COUNTS, BUT
SOMEHOW PLAY FOR THE
DRUG PRODUCT.
IT IS A HYBRID.
>> SO, THE CLINICAL

English: 
DEVELOPMENT OF ANY DRUG
OR BUY LOGIC, NEEDS A
COMMERCIALZATION PATH.
SO, TO HAVE A CLEAR
COMMERCIALZATION PATH,
ALWAYS INVOLVES
INDUSTRY, AND/OR FLAN
PEE.
AND THE REGULATORY PATH
HAS TO BE CLEAR.
>> The Moderator: NOW TWO
QUESTIONS VERY SIMILAR, SO I
WILL TRY TO PUT THEM TOGETHER.
>>> WILL THE COST OF
THIS PROCEDURE ALLOW A
LINE BETWEEN THOSE WHO
CAN AFFORD IT AND THOSE
WHO CANNOT, WOULD IT
MAKE THOSE IN POVERTY
MORE SUSCEPTIBLE
DISEASES, AND NOT
GETTING TREATMENTS.
THE SECOND ONE IS
SIMILAR.
>> I WILL RAISE MY
PEDIATRICIAN FLAG, IF IF
WE HAD UNIVERSAL HEALTH
CARE.

English: 
path they usually unfortunately always involves
industry and at times really more often philanthropy.
The other thing, which has been discussed
already today a little bit, is the regulatory
path has to be pretty clear. Without those
two things, it’s almost impossible to get
a clinical trial run in this country.
Jean Nagelkirk:
Now there are two very similar questions so
I’ll try to put them together. Would the
cost of this procedure allow a line between
those who can afford it and those who cannot?
Would it make those in poverty more susceptible
to diseases or not getting the appropriate
treatments and the second one is very similar.
Dr. Porteus:
So I’m going to raise my pediatrician flag,
Yay for universal healthcare. If we had universal
healthcare that question would not be relevant.
So I’m going to stand by that answer but
I will go back to issue of that’s for citizens
for people in the US or in people who live
in countries with good healthcare systems.
How do we get this to patients? Most patients

English: 
with sickle cell disease live in Africa and
India. How are we going to get the process
streamlined enough so it can be delivered
to people in countries where healthcare resources
are minimal, and how do we do it in a way
that’s cost effective? So I think the question
is to be solved. I think there are going to
be questions that are answered by people who
are in high school and college right now.
Jean Nagelkirk:
Bone marrow transplant programs have been
limited by certificate of need programs resulting
in financial gain for some institutions. Should
financial profit be a factor in democratizing
the gene editing world?
Dr. Porteus:
Yeah, it’s another spot-on question and
it goes I guess to use from the Belmont criteria,

English: 
I WILL STAND BY THAT
ANSWER.
THAT'S FOR PEOPLE IN THE
U.S., RATHER THAN PEOPLE
WHO LIVE IN COUNTRIES
WITH GOOD HEALTH CARE.
HOW WILL WE GET THE
PROCESS STREAMLINED
ENOUGH TO BE DELIVERED
IN COUNTRIES, WHERE
HEALTH CARRIE SOURCES
ARE MINIMAL, AND HOW DO
WE DO IT IN A WAY THAT
IS COST EFFECTIVE.
QUESTIONS TO BE SOLVED.
I THINK THERE WILL BE
QUESTIONS ANSWERED BY
PEOPLE WHO ARE IN HIGH
SCHOOL AND COLLEGE RIGHT
NOW.
>> The Moderator: OKAY, THIS ONE
IS BONE MARIO TRANSPLANT
PROGRAMS ARE LIMITED EARTH IS OF
NEED PROGRAMS, RESULTING IN
FINANCIAL GAIN FOR SOME
INSTITUTIONS.
SHOULD FINANCIAL PROFIT

English: 
the issue of justice. Should we only be bringing
therapies to market that can make a company
a profit? I hope not. In fact, I really hope
not because we’ve already seen, let me step
back a little bit. The gene therapy drug that’s
been approved in Europe for the treatment
of a form of bubble boy disease called ADA-SCID,
was licensed by GlaxoSmithKline, GSK. They
helped develop the product and they took it
through registration and they can sell it
and they can deliver it and sell it as a drug
in Europe. They’ve backed out and said we
don’t think that this will make us any money
and so we’re not going to sell it anymore.
And so they’re looking to sort of spin out
a company that will deliver it. There may
be a new model; maybe I’m just too idealistic,
that we’re going to have to have drug companies

English: 
BE A FACTOR IN
DEMOCRATIZING?
>> IT IS ANOTHER SPOT ON
QUESTION, I GUESS TO USE
FROM THE BELL MONTH
CRITERIA, THE ISSUE OF
JUSTICE.
AND SHOULD WE ONLY BE
BRINGING THERAPIES TO
MARKET, THAT CAN MAKE A
COMPANY A PROFIT.
I HOPE NOT.
IN FACT, I REALLY HOPE
NOT, BECAUSE WE'VE
ALREADY SEEN -- LET ME
STEP BACK A BIT.
THE GENE THERAPY DRUG
APPROVED IN EUROPE FOR A
TREATMENT OF BUBBLE BOY
DISEASE, CALLED ADA
SKID, WAS LICENSED BY
GLASGOW SMITH KLEIN,
THEY HELPED DEVELOP THE
PRODUCT AND TOOK IT
THROUGH REGISTRATION,
AND THEY CAN SELL IT IN,
AND DELIVER IT, SELL IT
AS A DRUG IN EUROPE.
THEY HAVE BACKED OUT,
AND THEY SAID, THIS WILL
NOT MAKE US MONEY, SO WE
DON'T WANT TO SELL IT

English: 
that deliver drugs at cost without looking
to have a profit. Who is going to do that?
I’m not sure, but it also gets to the point
that of those 10,000 genetic diseases, sickle
cell disease, thalassemia, certain others
are common enough that biotech pharma are
going to be interested because they’re going
to be able to make money. But 9,900 of them
don’t fall in that category and I think
we have to find a solution to be able to develop
curative therapies for diseases that might
only affect 10 or 20 people a year around
the world. We don’t have that model right
now in the healthcare system.
Jean Nagelkirk:
With genetic counseling in the future could
couples have genetic changes made in egg/sperm
to prevent hereditary diseases, high lipids,
Parkinson’s, Alzheimer’s, diseases of
aging?

English: 
ANY MORE.
SO, WE ARE LOOKING FOR A
COMPANY TO SPIN OUT AND
DELIVER IT.
>>> WE WILL HAVE TO HAVE
DRUG COMPANIES THAT
DELIVER DRUGS AT COST
WITHOUT LOOKING FOR A
PROFIT.
WHO WILL DO THAT, I AM
NOT SURE.
IT GETS TO THE POINT OUT
OF THOSE 10,000 GENETIC
DISEASES, SOME ARE
COMMON ENOUGH THAT THEY
ARE BIO TECH FARM MA
WILL BE INTERESTED,
BECAUSE THEY WILL BE
ABLE TO MAKE MONEY.
9,900 OF THEM DON'T FALL
INTO THAT CATEGORY.
I THINK WE HAVE TO FIND
A SOLUTION TO DEVELOP
CURE TIFF PHARMACIES,
THAT CAN HELP PEOPLE
AROUND THE WORLD.
WE DON'T HAVE THAT RIGHT
NOW IN THE HEALTH CARE
SYSTEM.
>> The Moderator: WITH GENETIC
COUNSELLING, IN THE FUTURE,
COULD COUPLES HAVE GENETIC

English: 
Dr. Porteus:
Whew. I’m going to be brain dead. These
are absolutely great questions. A lot in that
question. First of all, most cases of Alzheimer’s
are not genetic. Most cases of Parkinson’s
are not genetic. Most neurodegenerative diseases
are not genetic. That being said, a small
fraction are and so then could we use genome
editing to prevent somebody from developing
Alzheimer’s by editing sperm or egg to create
embryos who would not be at risk of developing
genetic Alzheimer’s, genetic Parkinson’s,
or genetic neurodegenerative diseases. That’s
really complicated right because you’re
doing something before birth to treat a disease
that’s going to show up 50, 60, 70, 80 years

English: 
CHANGES MAKE IN EGG SPERM, TO
GET RID OF SOME DISEASES?
>> SO,
--
>> I'M GOING TO BE BRAIN
DEAD.
THESE ARE GREAT
QUESTIONS.
A LOT OF GREAT
QUESTIONS.
FIRST OF ALL, MOST CASES
THEY ARE NOT GENETIC,
PARKINSONS ARE NOT
GENETIC.
THAT BEING SAID, A SMALL
FRACTION ARE.
SO THEN, COULD WE USE
GENOME EDITING TO
PREVENT SOMEBODY FROM
DEVELOPING ALL BY
EDITING SPERM OR EGG TO
CREATE, TO CREATE
EMBRYOS, WHO WILL NOT BE
AT RISK TO GET GENETIC
ALL, OR PARKINSON'S, OR

English: 
later. I think we need to know a lot more
about the safety of genome editing before
you’d want to take on something like that.
You’d want to make sure again the first
criterion is there’s no other reasonable
alternative. One of the things I forgot to
mention is that if we got really good at somatic
cell editing, we wouldn’t have to do germ
line editing. So, for example, if one could
figure out how to do in vivo editing of neurons
to take care of the synuclein mutation
or a parkin mutation, then we wouldn’t have
to go back to germ line editing. So the better
we get at somatic cell editing, the less need
or less drive there will be for germline editing.
Dr. MacKeigan:
I think it also raises the point back to gene
therapy is the effective targeting and delivery
vehicles of this technology is really going
to be the limitation is what we all see now
in front of us is that the specificity and
the precision and the safety are there. It’s

English: 
GENOME DISEASES.
>>> THAT'S REALLY
COMPLICATED, RIGHT.
YOU ARE DOING SOMETHING
BEFORE BIRTH TO TREAT A
DISEASE THAT WILL SHOW
UP 40, 50, 60 YEARS
LATER.
I THINK WE NEED TO KNOW
ABOUT THE SAFETY OF
GENOME EDITING BEFORE
YOU WOULD WANT TO TAKE
ON SOMETHING LIKE THAT.
YOU WILL WANT TO MAKE
SURE AGAIN, THE FIRST
CRITERIA, THERE IS NO
OTHER REASONABLE
ALTERNATIVE.
>>> ONE OF THE THINGS I
FORGOT TO MENTION, IF WE
GOT GOOD A SOMATIC CELL
EDITING, WE WOULDN'T
HAVE TO DO GENOME
EDITING.
>>> WE WOULDN'T HAVE TO
GO BACK TO GENOME
EDITING.
THE BETTER WE GET AT
SOMATIC EDITING, THE
LESS NEED FOR GENOME
EDITING.
>> YES, AND EFFECTIVE
TARGETING AND VEHICLES

English: 
FOR THIS TECHNOLOGY, IS
REALLY GOING TO BE AT
THE LIMITATION.
THE SPES TEE AND
DELIVERY PAY LOAD, AND
THAT HAS BEEN AROUND FOR
30 YEARS, FINDING AN
EFFECTIVE WAY TO DELIVER
THESE APPROACHES.
>> The Moderator: AT WHAT -- FOR
EXAMPLE, WOULD A TRANS
INDIVIDUAL ATTEMPTING SEX CHANGE
BE CONSIDERED ENHANCEMENT?
>> I DON'T KNOW.
YEAH, I DON'T THINK SO.
I THINK THAT IS
REALIZING ONE'S
POTENTIAL.
I DON'T THINK THAT IS AN
ENHANCEMENT.
>> The Moderator: DOES GENE
EDITING AFFECT THE OPEN PI
GENOME?
>> WHAT I DIDN'T TALK
ABOUT TODAY.
CERTAINLY THE PROCESS OF
GENE EDITING, MAKING A
BREAK IN A GENE DOES
CHANGE THE OPEN PI
GENETIC SURROUNDING THAT

English: 
now we need delivery payload and that’s
been around for 30 years that we haven’t
found a way to effectively deliver these gene
therapy approaches.
Jean Nagelkirk:
At what point does a treatment fall into enhancements?
For example, would a trans individual attempting
sex change be considered enhancement?
Dr. Porteus:
I don’t think so. I think that’s realizing
one’s potential, but I don’t think that’s
an enhancement.
Jean Nagelkirk:
Does gene editing or can it affect 
the epigenome?
Dr. Porteus:
Certainly the process of gene editing, making
a break in a gene, does change the epigenetic
surrounding that break. It’s thought that
that’s a transient change and will be reversed
once the break is repaired and everything
goes back to normal. That truly is a question

English: 
that needs to be studied further. Certainly
if you’re modifying a gene and having that
cell behave differently may have epigenetic
effects throughout the genome that we don’t
understand. So certainly an area of interest.
The other thing that we didn’t discuss is
people often talk about epigenome editing,
which is sort of a weird term, but it’s
a hybrid. Which is not to use the Cas9 protein
as a way of making a break in the DNA and
changing the DNA sequence, but instead using
the Cas9 system to bring an epigenetic modifier
to a certain site and change the epigenetics
around a certain site and change the way that
gene is expressed or how long it’s expressed
or to what level it’s expressed. It wouldn’t
be the same as genome editing in the sense
of changing the DNA sequence, but it would
be a way of changing the way a cell functions
without having to change the DNA sequence

English: 
BREAK.
IT IS THOUGHT, THAT THAT
IS A TRANSIENT CHANGE
ONCE THE BREAK A
REPAIRED AND EVERYTHING
IS BACK TO NORMAL.
THAT IS A CHANGE THAT
NEEDS TO BE STUDIED
FURTHER.
>>> CERTAINLY, IF YOU
ARE MODIFYING A GENE AND
HAVING THAT CELL BEHALF
DIFFERENTLY, MAY HAVE EP
PI GENETIC EFFECTS,
MAYBE OF INTEREST.
>>> THE OTHER THING WE
DIDN'T DISCUSS, IS OPEN
PI GENOME EDITING, WHICH
IS A WEIRD TERM.
WHICH IS NOT TO USE THE
CAST 9 PROTEIN AS A WAY
OF MAKING A BREAK IN THE
DNA, AND CHANGING THE
DNA, BUT INSTEAD USE THE
SYSTEM TO BRING THE OPEN
PI GENOME GENOME EDITING
AND CHANGE THE GENEICS
AROUND THAT SIGHT.

English: 
IT WOULDN'T BE THE SAME
AS GENOME EDITING IN
TERMS OF CHANGING THE
SEQUENCE.
THERE IS A LOT OF
RESEARCH ABOUT HOW WE
WOULD DO THAT.
IN TERMS OF
TRANSLATIONAL
APPLICATIONS IT IS WAY
BEHIND.
IT IS UNCLEAR HOW AND
WHEN YOU WOULD USE THAT.
>> I THINK WE TALKED
ABOUT IT, D CAST 9, D
STANDS FOR DEAD, YOU CAN
USE THAT ENZYME ALONG
WITH THE GUY NAY, WHICH
COULD IDENTIFY MARKS ON
DNA, OR MODIFY DNA,
WHICH WOULD EXPRESS
GENTLEMAN MODEM
EXISTENCE.
>> I THINK THAT WOULD BE
A VALUABLE RESEARCH
SEARCH.
I DON'T SEE THE
APPLICATION ANYTIME
SOON.
>> The Moderator: IN THE FIELD
OF GENTLEMAN MODEM MIX, IS IT
PROGRESSING AT AN ACCEPTABLE

English: 
of a cell and there’s a lot of research
about how we would do that. In terms of translational
applications, it’s a lot farther behind
because it’s unclear exactly when or how
you would use that.
Dr. MacKeigan:
I think we talked about it in the afternoon
session about this dCas9, the D stands for
dead and it doesn’t have the enzymatic activity
to cut the DNA. You can use that enzyme along
with the guide RNA to bring what we call payload,
that could modify both marks on DNA or modify
marks on histones that would affect gene expression
versus DNA sequence. I agree that could be
a very valuable research tool, but I don’t
see the clinical application anytime soon.
Jean Nagelkirk:
Is the field of genomics progressing at an
acceptable rate? If not, what is the greatest
constraint? Is it trained scientists, lack
of equipment, lagging knowledge? Inability
to examine all of the data generated?

English: 
Dr. MacKeigan:
I guess one comment would be is with what
we sort of emphasized earlier also is what
we can do now for the cost of what we can
do is just mind boggling with the drop in
prices of say genome sequencing to approach
just over $1,000 for a genome where, you know,
20 years ago it was a $100 million operation.
So now in our laboratory to give you an example,
we looked at the rare disease tuberous sclerosis
and within about a 2 ½ year period we were
able to provide more information, sequencing
data on those disease populations than was
collected prior. And so that was one of the
things, the barrier was active patients that
want to participate in rare disease, they’re
usually all very active and want to participate
but finding patients with a rare disease is
difficult so you have to have sort of a national
search for those patients. The second thing
is money. It turns out that if you want to
get politically active that our National Institute

English: 
RATE?
IF NOT, IT IS LACK OF
KNOWLEDGE, INABILITY TO
ACCELERATE, OR EXAMINE
ALL THE DATA AGAIN
RATED?
>> ONE COMMENT WOULD BE,
SORT OF EMPHASIZE
EARLIER, WHAT WE CAN DO
NOW, FOR THE COST WHAT
WE CAN DO, IS MIND
BOGGLING, OF GENOME
SEQUENCING, AND 20 YEARS
AGO, IT WAS HUNDRED
MILLION DOLLAR
OPERATION.
NOW IN OUR LABORATORY,
TO GIVE YOU AN EXAMPLE,
WE LOOKED AT THE RARE
DISEASE, TUBE BETTER
SCLEROSIS, WE WERE ABLE
TO PROVIDE MORE
INFORMATION ON THE GENE
OPERATIONS THAT WAS
COLLECTED PRIOR.
THAT WAS ONE OF THE
THINGS, THE BARRIERS,
ACTIVE PATIENTS THAT
WANT TO ACTIVE IN RARE
DISEASE, BUT FINDING

English: 
PATIENTS WITH A RARE
DISEASE IS DIFFICULT.
YOU HAVE TO HAVE A
NATIONAL SEARCH FOR
THOSE PATIENTS.
>>> THE SECOND THING IS
MONEY.
IF YOU WANT TO GET
POLITICALLY ACTIVE, OUR
NATIONAL INSTITUTE OF
HEALTH, PROVIDES MONEY
FOR BIO RESEARCH, BUT
COST OF RESEARCH
EQUIPMENT, WE HAVE AN
ANNUAL DROP OF A FEW
PERCENT EACH YEAR HOW
FAR OUR RESEARCH DOLLARS
WILL GO.
NOT ONLY IS RESEARCH
VERY EXCITING RIGHT NOW,
AND WHAT WE TRANSLATE,
THE COMPETITION OF
DOLLARS IS HIGH.
WE ARE FUNDED BY THE
NATIONAL CANCER
INSTITUTES, AND AT A PAY
LINES, IS APPROACHING
8%.
THAT IS 29% OF PEOPLE,
WHO WORK THEIR WHOLE
CAREERS AND LIVES FOR
THIS, AND THE PEOPLE IN
THEIR LABS CANNOT
COMPETE FOR FUNDING
SUCCESSFULLY.
BASICALLY ONE IN TEN

English: 
of Health provides a wealth of resources for
biomedical research in this country but with
cost of research equipment we have an annual
drop of a few percent every year in how far
research dollars will go. So not only now
is research quite exciting in what we can
discover and maybe translate, the competition
for dollars is very high. An example would
be we’re funded by the National Cancer Institutes
and the pay line which is what who gets funded
and who doesn’t is approaching about 8%.
That means 92% of people that are very talented,
that have great ideas, that worked their whole
careers and lives for this, and the people
they have in their labs and employ cannot
compete for funding successfully. So basically
1 in 10 researchers out there gets federal
funding right now.
Dr. Porteus:
I’ll agree exactly. The other thing I would

English: 
add is going back to the earlier question
about developing therapies for rare diseases,
we need to train and fund translational medicine
and people trained in translational medicine.
So the NIH has historically been we need more
money, get all that, has historically been
good at funding discoveries and biotech and
pharma have been pretty good. You know, not
perfect, at creating drugs for common diseases.
But what we’ve been missed is that what
we need now particularly with I think genome
editing is a large cohort of people who are
trained and ambitious and driven to using
these new technologies to bring therapies
to rare diseases because as I said, I think
we can affect the lives of not only those
patients but large communities, but we’re
missing that. It’s hard to get trained in
that right now.
Jean Nagelkirk:

English: 
RESEARCHERS GET FEDERAL
FUNDING RIGHT NOW.
>> I WILL AGREE.
THE OTHER THING I WOULD
ADD, GOING BACK TO THE
EARLIER QUESTION, P.M.
DEVELOPING THERAPY FOR
RARE DISEASES, WE NEED
TO TRAIN AND FUND MORE
EXPERTS -- FUND
TRANSLATIONAL MEDICINE,
AND PEOPLE TRAINED IN
TRANSLATIONAL MEDICINE.
THE NHR, HISTORICALLY,
HAS BEEN GOOD AT FUNDING
DISCOVERS.
PIE YO TECH AND FARM MA,
HAVE BEEN GOOD, NOT
PERFECT, AS CREATING
DRUGS FOR COMMON
DISEASES.
>>> BUT, WHAT WE HAVE
MISSED, WHAT WE NEED
NOW, PARTICULARLY WITH
GENOME EDITING IS A
LARGE COHORT OF PEOPLE
WHO ARE TRAINED,
AMBITIOUS AND DRIVEN TO
USE NEW TECHNOLOGIES TO
BRING THERAPIES TO RARE
DISEASES.
BECAUSE, AS I SAID, WE

English: 
Ok, speaking to minimizing inequality in genome
editing, how do you feel these gaps can be
closed or reduced in the future of genome
editing?
Dr. Porteus:
Well, I’ll probably get stuff thrown at
me. One way is 
to start taking the technology and moving
it into places like China, India, and Brazil
which are second-world. I hate that term,
but let’s just say not maybe where we’re
at but a lot of smart sophisticated people
with a lot of patients. You know they can
make generic drugs pretty cheap. Maybe they
can take the process that we’re doing in
a very expensive fashion in the US and find
ways of doing it much more cost effectively.
Maybe one of the ways of solving this problem

English: 
AFFECT THE LIVES OF NOT
ONLY PATIENTS BUT LARGE
COMMUNITIES.
WE ARE MISSING THAT.
IT IS HARD TO GET
TRAINED IN THAT RIGHT
NOW.
>> The Moderator: SPEAKING TO --
HOW DO YOU FEEL THE GAPS CAN BE
CLOSED IN THE FUTURE OF GENOME
EDITING?
>> WELL, YOU KNOW,
PROBABLY GET STUFF
THROWN AT ME.
ONE WAY IS FOR -- TO GO
FROM, TO START TAKING
THE TECHNOLOGY AND
MOVING IT TO PLACES TO
CHINA, INDIA, AND
BRAZIL.
SECOND WORLD.
>>> I EVEN HATE THAT
TERM.
NOT MAYBE WHERE WE ARE
AT, A LOT OF SMART
PEOPLE WITH A LOT OF
PATIENTS, THEY CAN MAKE
GENEIC DRUGS AND MAKE
THEM CHEAP.

English: 
>>> MAYBE GETTING OTHER
COUNTRIES TO ADOPT IT
AND THEY WILL MAKE IT
WORK IN THEIR
COMMUNITIES.
>> The Moderator: THE LAST
QUESTION BEFORE OPEN MIC, DO YOU
PERCEIVE GENOME EDITING
TECHNIQUES BECOMING TRADEMARKED
OR --
[INDISCERNIBLE]
DO YOU SEE THAT COMING
SOON?
>> I THINK COMMERCIAL --
I KNOW, THROUGH MY
INTERACTIONS WITH THE
BUY YES TECH FIRMS THAT
ARE FOUNDED AROUND
GENOME EDITING, THEY
DON'T WANT TO COME NEAR
THAT RIGHT NOW.
SO, I DON'T SEE IT
COMING SOON.
I THINK THE QUESTION IS,
IF IN TEN YEARS, THERE
IS A HUNDRED CLINICAL

English: 
of distribution is to get a medical center
in India to adopt this and a medical center
in Brazil and a medical center in China to
adopt it, and they will figure out ways of
making it work for their communities.
Jean Nagelkirk:
The last question before we do open mic is
basically very similar to an earlier one.
Do you perceive gene editing technology becoming
trademarked or commercialized to an extent
where possible so the opportunity for personal
and cosmetic pieces. Do you see that coming
soon?
Dr. Porteus:
I know through my interactions with the biotech
firms that are founded around genome editing
and the pharmaceutical firms founded around,
they don’t want to come near that right
now. So I don’t see it coming soon, but
I think the question is is if in 10 years
there are 100 clinical trials showing that
this is all safe will someone say ah, now
I’m going to start a cosmetic company based
on genome editing? I don’t know.

English: 
TRIALS SHOWING IT IS ALL
SAFE, SOMEONE WOULD SAY,
I WILL START A COSMETIC
COMPANY BASED ON GENOME
EDITING, I DON'T KNOW.
>> The Moderator: NOW IS THE
OPPORTUNITY IF YOU WANT TO HAVE
A QUESTION FROM THE MIC, RAISE
YOUR HAND AND SOMEONE WILL COME
TO YOU?
DO WE HAVE ANY
ADDITIONAL QUESTIONS?
>> THERE IS ONE OVER
HERE.
>> I WANTED TO THANK YOU
FOR THAT.
AND DOING DOUBLE DUTY.
JEFF, THANKS FOR
PINCH-HITTING, AS WELL.
>>> WHEN WE THINK OF
HUNTING TONS AND CYCLE.
IT IS SPECIFIC, AND WE
KNOW HOW TO DO THAT.
I AM ANXIOUS TO SEE THE

English: 
Jean Nagelkirk:
Ok, now is the opportunity if you want to
have a question from the mic, raise your hand
and someone will come to you. Do we have any
additional questions or are we…There’s
one there, John…
John:
I wanted to thank you for coming. First of
all, I think what you do is fantastic and
you know from my perspective the way you explained
it made great sense to me and I really for
all I’ve heard about genomic editing it
just flies over my head and I have a much
better grasp on that so I just wanted to thank
you for that and for doing double duty. Jeff,
thanks for pinch hitting as well. So the question
I had was when we think about things like
Huntington’s and sickle, boy it’s really
specific. We know how to do that and anxious
to see the results of the fruits of that labor
coming forth. But I was sitting here thinking
about mental health and thinking about alcoholism.

English: 
RESULTS OR FRUITS OF
THAT LABOR COMING FORTH.
I WAS THINKING ABOUT
MENTAL HEALTH.
THINKING ABOUT
ALCOHOLISM.
THINKING ABOUT OPIOID
ADDICTION, AND THINGS
THAT RAVAGE OUR COUNTRY
RIGHT NOW.
MANY PEOPLE SPECULATED
AND DEMONSTRATED, THERE
IS SOME ELEMENT OF
GENEIC HICCUP THAT IS A
PREDISPOSITION FOR
ADDICTION.
IS THAT SOMETHING WE ARE
BEGINNING TO BROACH, OR
IS IT REALLY THE CLEARLY
PHYSICALLY RELATED
DEFECTS THAT YOU ARE
LOOKING AT NOW?
>> YEAH, I MEAN, I LOVE
GENOME EDITING.
I SPEND WAY TOO MUCH
THINKING ABOUT IT.
I DON'T THINK IT IS A
MAGIC WAND THAT WILL
SOLVE ALL THE PROBLEMS
THAT WE HAVE, LIKE MANY
OF WHICH YOU HAVE
MENTIONED.
ARE THERE PERHAPS,
POTENTIAL STRATEGIES

English: 
Thinking about opioid addiction and some of
the things that really ravage our country
right now. Many people have speculated and
some have demonstrated that there is in fact
some element of genetic underlying hiccup
that results in a predisposition for addiction.
Is that something that we’re even beginning
to broach into or are we looking just as a
really clearly physically-related defects
that you’re looking at now.
Dr. Porteus:
I love genome editing. I spend way too much
time thinking about it, but I don’t think
it’s a magic wand that’s going to solve
all of the problems that we have, many of
which you mentioned. Are there perhaps potential
strategies that can be utilized for these
diseases in the future? Perhaps. But I think
if I came up here and told you that genome
editing was the solution to everything you

English: 
THAT COULD BE UTILIZED
FOR THESE DISEASES IN
THE FUTURE?
PERHAPS.
I THINK IF I CAME UP
HERE AND TOLD YOU GENOME
EDITING WAS THE SOLUTION
TO EVERYTHING, YOU
SHOULD PROBABLY THROW ME
OUT.
I THINK YOU HAVE
HIGHLIGHTED SOME THINGS,
AND MAYBE IT GOES BACK
TO THE EARLIER POINT, I
LOVE THAT LA MILES AN
HOUR ALEXANDER WAS
EXCITED BY GENOME
EDITING.
I WISH HE WAS MORE
EXCITED TO SOLVE THE
PROBLEMS YOU WERE
MENTIONING.
AND EQUAL EXCITEMENT
TACKLING THOSE PROBLEMS
THAN FIGURING OUTCAST 9.
UNFORTUNATELY WE HAVE A
MISMATCH HERE.
>> I THINK YOU BROUGHT
UP
EARLIER, --
CERTAINLY, MAYBE A
QUESTION FOR YOU,
MATTHEW.
HOW MANY GENES, DO YOU
THINK YOU COULD REPAIR
IN ONE SETTING?
8 OR 6 OR AM I WAY OFF?

English: 
should probably throw me out. That’s just
not going to happen. I think you’ve highlighted
some things and maybe it goes back to the
earlier point is that I love that this Lamar
Alexander is excited about genome editing.
I wish he was more excited about putting in
all the hard work that needs to be done to
solve the problems that you were mentioning
and I wish there was equal excitement about
tackling those problems as there are to figuring
out what the next great variant of Cas9 is.
Unfortunately we have a mismatch here.
Dr. MacKeigan:
You talk about polygenic diseases and environment
interactions versus a monogenic correction
of disease gene. Certainly maybe a question
for you Matthew, how many genes do you think
you could repair in one setting? Is it 8,
is it 6? Am I way off?
Dr. Porteus:
So right now we’re up to 4.
Dr. MacKeigan:
Ok.
Dr. Porteus:

English: 
>> SO, RIGHT NOW, WE ARE
UP TO 4.
BUT ONLY A SMALL
PERCENTAGE OF CELLS.
>> GET ALL 4, YES.
>> SOME GET ONE, SOME
GET 1, SOME 2, SOME GET
4.
THE MORE GENES YOU TRY
TO MODIFY AT ONCE, THE
MORE CHAOS YOU CREATE,
AS WELL.
>>> WHAT I DIDN'T
MENTION, IF YOU MAKE TWO
BREAKS IN THE GENOME AT
THE SAME TIME, AT SOME
FREQUENCY, THE CELL
WON'T PUT THE TWO ENDS
BACK TO WHERE THEY ARE
SUPPOSED TO.
THE MORE THINGS YOU DO
AT ONCE, THE MORE SORT
OF GENEIC CHAOS YOU
MIGHT CREATE, SO THAT IS
PROBABLY A LIMITING
FACTOR.
>>> I ALSO THINK, MY
POINT ABOUT HUMANITY IS

English: 
But only a small percentage of cells to get
all four. Some get 1, some get 2, some get
3, and some get 4. The other problem also
is the more genes you try to modify at once,
the more genetic chaos you create as well
because what I didn’t mention is that if
you make two breaks in the genome at the same
time at some frequency the cell won’t put
the two ends back together where they’re
supposed to. It’ll swap them. And so you’ll
create chromosomal translocations and chromosomal
deletions. The more things you do at once,
the more sort of genetic chaos you might create
and so then that becomes I think a limiting
factor in terms of going after polygenic diseases.
I also think that, my point about humility
is that we don’t understand that polygenic
variance that might predispose you to a condition

English: 
WE DON'T UNDERSTAND,
VARIANCE THAT MY POLL
AGAIN I CAN VARIANCE, AM
I PRE-DISPOSED TO 21st
AMERICA MAY BE A HEALTHY
COMBINATION OF TRAITS IN
A DIFFERENT ENVIRONMENT.
FOR US TO THINK THIS SET
OF TRAITS IS ALWAYS PATH
LOGIC IS OVERESTIMATING
OUR KNOWLEDGE THAT MINOR
EFFECTS THAT DO.
>> The Moderator: ARE THERE ANY
OTHER QUESTIONS?
DR. TOMATIS.
>> YOU VERY BRIEFLY
MENTIONED UNIVERSAL
HEALTH CARE.
COULD YOU BE SO KIND TO
EXPAND WHAT IS YOUR
THOUGHT ABOUT?
>>
[ LAUGHTER ]
I KNEW I SHOULDN'T HAVE
MENTIONED THAT.
>>> AGAIN, IT COMES FROM
THE, YOU KNOW, MY
BACKGROUND AS

English: 
that exists in 21st century America may be
a healthy combination of traits in a different
environment and for us to think that this
set of traits is always pathologic would be
I think overestimating our knowledge of what
these variants that have minor effects in
combination actually do.
Jean Nagelkirk:
Are there any other questions for us? Dr.
Tomatis?
Dr. Tomatis:
Dr. Porteus, you very briefly mentioned universal
healthcare. Could you be so kind to expand
and what is your thought about…
Dr. Porteus:
I knew I shouldn’t have mentioned that.
It really goes, again it comes from my background
as a pediatrician and my interest in developing

English: 
therapies for rare diseases and a concept
of justice that if we’re going to develop
therapies they shouldn’t be available to
somebody just because they happen to be employed
by Facebook in Palo Alto, CA and instead of
being in Oakland, CA where you know they’re
unemployed. The only way I can think of reliably
doing that is if there is some sort of universal
healthcare. How to implement that in this
country? I’m staying out of that entirely.
That’s my pediatrician speaking.
Jean Nagelkirk:
Other questions? There are two I see – one
up front and one…
Audience:
Hopefully as a comical relief for you, how
insane did you go when you saw the gene theory
from Jurassic Park?
Dr. Porteus:
Ya know, I haven’t seen the movies so I
don’t know.
Dr. MacKeigan:

English: 
PEDIATRICIAN, AND MY
INTEREST IN DEVELOPING
THERAPIES FOR RARE
DISEASES, AND THE
CONCEPT OF JUSTICE.
IF IF WE DEVELOP
THERAPIES, THEY
SHOULDN'T BE AVAILABLE
TO SOMEBODY JUST BECAUSE
THEY HAPPEN TO BE
EMPLOYED BY FACEBOOK IN
PAL ALTO CALIFORNIA, AND
INSTEAD OF BEING OAKLAND
CALIFORNIA, WHERE THEY
ARE UNEMPLOYED.
>>> THE ONLY WAY I CAN
THINK OF OF RELIABLY, TO
DO IT IF THERE IS SOME
SORT OF HEALTH CARE.
HOW TO IMPLEMENT THAT, I
AM STAYING OUT OF THAT
ENTIRELY.
THAT'S MY PEDIATRICIAN
SPEAKING.
>> The Moderator: OTHER
QUESTIONS?
THERE IS TWO, I SEE.
ONE UP FRONT.
>> HOPEFULLY AS A
COMICAL RELIEF FOR YOU,
HOW INSANE DID YOU GO
WHEN YOU SAW THE GENE

English: 
THEORY FROM GENTLEMAN
RASE SICK PARK?
>> I HAVEN'T SEEN THE
MOVIE, SO I DON'T KNOW.
>> GOING BACK TO THE
FIRST GENTLEMAN RASE
SICK PARK HERE?
>> SCIENTISTS DON'T
WATCH A LOT OF OF
MOVIES, WE DON'T HAVE A
LOT OF TIME FOR THAT.
WHEN I LIVED IN SAN
FRANCISCO, THAT'S WHAT
WAS -- CERTAINLY,
GENTLEMAN RASE SICK
PARK, IT HELPS SPARKS
FOR KIDS, IN BEING A
SCIENTIST.
MAYBE SCARY, TOO, AS A
MOVIE.
BUT, UM... .
>> MY CALF I CAN'T TELL
TO THAT, IS THOUGH, IS
THIS CONCEPT OR, I
THINK, I DON'T LIKE HOW
SOMETIMES GENEICS IS
DESTINY.
I THINK GENEICS -- I

English: 
Are we going back to the first Jurassic Park
here? Scientists don’t watch a lot of movies,
we don’t have a lot of time for that, but
we talked earlier Gattaca was a great movie.
When I lived in San Francisco that’s what
was playing at the theater and certainly Jurassic
Park. It helps your imagination. For kids
it sparks an interest in being a scientist,
maybe scared too at times with that movie,
but.
Dr. Porteus:
My caveat to that though …. 
I don’t like how sometimes genetics is destiny.
I think genetics is probability; it’s not
destiny. I think sometimes we as scientists
we allow the popular press to portray genetic
determinism. If you have this, then you’re
going to have that. For some of the diseases

English: 
we’ve talked about today, Huntington’s
disease, sickle cell disease, yeah it’s
nearly 100%. But most of the things that we
think give us our humanness are probabilistic.
I’d love if we could get away from thinking
about gene destiny, tight gene destiny relationships.
Audience:
I have a question actually about one of the
images you had. You had a graph that showed
the exons and introns and how when you had
the gene therapy put in it didn’t change
too much. It didn’t produce mutations. Just
kind of showing that, implying anyway, that
the resulting protein would still have the
same activity. The percentage for the exons
was very, very small, or introns, excuse me.

English: 
THINK AS SCIENTISTS, WE
ALLOW THE POPULAR PRESS
TO PORTRAY GENEIC
DETERMINISM.
FOR SOME OF THE DISEASES
WE TALKED ABOUT TODAY,
YEAH, IT IS NEARLY 100%.
MOST OF THE THINGS WE
THINK GIVE US OUR
HUMANNESS, ARE
PROBABILISTIC.
 I WOULD LOVE TO GET
AWAY FROM -- I WOULD
LOVE TO GET AWAY FROM
TIGHT GENE
RELATIONSHIPS.
>> I HAVE A QUESTION
ABOUT ONE OF THE
IMAGINES YOU HAD.
YOU HAD A GRAPH THAT
SHOWED THE EXAMINE
ONS,
AND WHEN YOU HAD THE
GENE THERAPY PUT IN AND
IT DIDN'T CHANGE TOO
MUCH.
IT DIDN'T PRODUCE
MUTATIONS.
JUST KIND OF SHOWING, OR
IMPLYING ANYWAY THAT THE
RESULTING PROTEIN WOULD

English: 
The changing between the percentages, and
I’m wondering if those were the same proteins
throughout…if those were the means of like
accumulation of all of them.
Dr. Porteus:
Ya know what, maybe after we’re done you
can point me and I can explain what that means
because I’m not exactly sure which one you’re
talking about. We can look at the graph.
Jean Nagelkirk:
Any other questions? Seeing none, I want to
thank you all for coming.

English: 
STILL HAVE THE SAME
ACTIVITY.
JUST THAT THE PERCENTAGE
FOR THE EXXONS OR
ENTERONS, EXCUSE ME.
THE CHANGING BETWEEN THE
PERCENTAGES.
I AM WONDERING IF THEY
WERE THE SAME PROTEINS
THROUGHOUT OR MEANS OF
OF AN ACCUMULATION OF
ALL OF THEM?
>> MAYBE AFTER WE ARE
DONE, YOU CAN POINT TO
ME, AND EXPLAIN WHAT IT
