Immortal Human Skin Cells
Miraculous Answer for Burn Victims?
skin cells that do not die at the University of Wisconsin, Madison,
provide a better and unlimited skin supply for burn victims? Healthy
skin supply is limited, demanding experiments seeded with autologous
keratinocyte skin cells to repair a burned shoulder.
is a holiday to celebrate the birth of the man named Jesus Christ,
long considered by many to be divine, even immortal. The New Testament
says his disciples heard Christ tell them that "whosoever believeth
in Him who sent me shall have ever lasting life." As if to prove
the lesson of his words, he also told the disciples that he would
die before them and then resurrect with new life to walk among
Bible also describes Abraham and his bloodline that included Methuselah
and Noah as living for centuries. In contrast, humans and most
other earth creatures seem to have such short lives. Could life
expectancy - even immortality - be a function of genetic sequencing
on chromosomes? Two important medical reports this month suggest
that genome sequencing can extend life, and human skin might even
be made immortal. Researchers at the University of Connecticut
Health Center in Farmington have announced that the life span
of fruit flies have been doubled when a gene was modified on a
single chromosome. The senior author of the study, Dr. Stephen
L. Helfand, said the gene mutation seems to work by restricting
calorie absorption on the cellular level. Consequently, there
is not as much weight gain, but the fruit flies' health and energy
are normal. "By the time that 80-90% of normal flies are dead,
these mutant flies are still doing just fine." Dr. Helfand thinks
his research might be applied to developing a pill which could
both extend human life and control weight.
more amazing is a completely accidental discovery of skin cells
that do not die at the University of Wisconsin in Madison. In
fact, Dr. Lynn Allen-Hoffmann - Professor of Pathology and director
of the laboratory in which the cells reside - calls them "immortal"
- immortal human skin. When the miraculous cells were still alive
and thriving after an entire year, instead of dying after a few
weeks like normal skin, the University of Wisconsin Alumni Research
Foundation patented the cells now known as "NIKS." That acronym
stands for Near-Diploid Immortal Keratinocytes. The acronym also
represents the lab's sense of humor. NIKS is SKIN spelled backwards.
all started in early 1996 at the end of a research project in
which Dr. Allen-Hoffmann and her lab assistants had been growing
human skin cells in culture dishes over several weeks. In one
set of dishes, she was testing a chemical additive on tissue.
Another series of dishes had nothing added so she would have a
normal control for comparison. Strangely, and still mystifying,
one of the control dishes was different from all others.
Allen-Hoffmann, Ph.D., Prof. of Pathology
University of Wisconsin Medical School, Madison, Wisconsin:
it was in one of those control cell plates that my technician, Sandy
Schlosser, noticed - and this was on the day we were literally going
to fix, and by fix I mean formaldehyde-preserve these cells which
would totally have terminated the experiment. Anything living in
there would have been killed. We noticed there was a small colony
of cells that had a phenotype that is called basal. They looked
as if they were actively growing. They were small and very uniform
in size and she came into my office and said, 'Lynn, come and take
a look.' And I went in and looked at this and she asked me what
it was and I said, 'You know, that looks like an actively growing
colony and this is very unusual. I don't know for sure what it is.'
Why would that colony be living when clearly all the other cells
in the dish were senescent?
dead. And I recognized this was clearly unusual, so we had many
replicate control dishes. So, I said, 'Go ahead and fix all the
other plates in the experiment.' And she looked at all the other
control dishes very carefully to see if there were any other colonies
and there weren't. So, we just had that one plate and she put it
back in the incubator.
about a week or so later, we came back and it was quite clear that
colony was growing and in fact, that colony produced enough cells
to essentially cover the surface of that plate. And it was at that
point in time that I recognized, 'This is quite unusual.'
instructed her to cryo-preserve the cells every other week, or every
other passage, so that we would generate a catalogue of these cells.
She did that and she did that for a full year continuously! And
after a year, we said, 'These cells by scientific definition had
achieved immortality.' Because that is a very long time for this
cell type to be living and actively growing at a consistent growth
rate. And it did grow at a very consistent growth rate, identical
to the parental cells from the tissue that we isolated the cells
from initially. And I anticipated at first that these cells would
be aberrant in some way in their characteristics.
THEY MIGHT BE CELLS THAT WERE PRE-CANCEROUS OR HAD A DEFECT?
And so some of the first experiments we did was to have these cells
at various passages karyotyped - that is, had their chromosomes
analyzed to see if there were any large lesions or additions and
whether the cells accumulated chromosomal abnormalities over this
long period in cultures over the year. And we did indeed find that
the cells had duplicated one section of the chromosome. And that
was chromosome 8 and it was a section of a long arm of chromosome
8. In looking at cells in different passages over the course of
that year, we found an unusual thing and that was that the cells
did not accumulate other growth chromosomal abnormalities and that
the cells maintained this extra piece of chromosome 8. So, we hypothesized
that this duplication of genetic material is important for the cells
to have the immortal phenotype that they possess.
A NORMAL HEALTHY PERSON, WHAT WOULD CHROMOSOME 8 DO?
is a complex question you just asked me, but suffice it to say that
it is reasonable to speculate that the extra expression of genes
that are coming from chromosome 8 perhaps play a role in the immortality
that has happened to these cells. And does it confer other characteristics
to the cells? That we have been investigating and we have stayed
quite focused on characterizing the features of skin cells because
this is what these cells are from, keratinocytes. They were derived
from skin tissue keratinocytes that my lab studies and so we wanted
to confirm that these cells are keratinocytes, which they are, and
we are in the really fortunate position of having the infant's original
foreskin cells with which to make comparisons to this cell line
that has arisen from them. We are in a very unique position to be
able to make that comparison and we have been making those comparisons.
what was astounding to us was that this cell line that has this
immortal growth characteristic is amazingly similar to the original
parental cells. We were expecting to see some biochemical differences,
some structural differences in the cells in culture, and we thus
far have not observed that. We have looked to see if they exhibit
any characteristics that would lead us to believe they are cancerous
or pre-cancerous and the answer to that is no.
THEN THE NEXT STEP IS: COULD YOU PRODUCE LARGE QUANTITIES OF NORMAL
HUMAN SKIN THAT COULD BE USED ON BURN VICTIMS?
and that is a really important question. We're doing animal grafting
studies now with the NIKS cell graft to determine if we can indeed
do that and if we can successfully get the cells grafted on to animal
models. We have a lot of really exciting work to be done yet with
regard to demonstrating that this will be a therapeutic value to
the medical community. And we're excited about positioning ourselves
so we can go forward with those types of experiments.
YOU THINK BASED ON THE WORK YOU'VE DONE SO FAR THAT THE IMMORTAL
CELLS CAN BECOME A KIND OF INFINITE SUPPLY OF HUMAN TISSUE TO BE
USED IN BURN VICTIMS?
would be a dream come true. That would be a dream come true for
a large number of people. One of the advantages of this cell line
is that you don't have to harvest any more tissue. We have the cells.
We know they don't carry viruses. They have been characterized to
see if they contain viruses such as human papilloma virus which
causes warts on our skin and also causes cervical cancer in women.
NIKS cells do not possess that virus in that class. They don't possess
the hepatitis virus. They don't possess HIV. So, this is wonderful!
Or other pathogens we've tested for so far.
YOU'VE GOT A CLEAN LINE . . .
yes, for the things we've tested so far.
CELLS PERPETUATING HUMAN SKIN CELLS. AND SO THAT I'M CLEAR AND THE
GENERAL AUDIENCE IS CLEAR, AFTER FIVE YEARS, YOU HAVE THE SAME STOCK
OF THAT INFANT'S FORESKIN AND THOSE CELLS ARE NOT SHOWING ANY SIGNS
OR INCLINATION OF DYING AS NORMAL HUMAN TISSUE WOULD . . .
IF YOU CAN, AS YOU SAID, GENETICALLY ENGINEER THEM SO THEY WOULD
GROW INTO MULTIPLE LAYERED NORMAL HUMAN SKIN THAT COULD BE USED
IN BURN VICTIMS . . . THAT WOULD BE TERRIFIC.
DOES THAT MEAN THAT SKIN GRAFTED ONTO A BURN VICTIM WOULD ALSO GROW
FOREVER WITHOUT DYING AND THERE WOULD BE NO AGING AND NO WRINKLING?
Well, that's a big question. I don't know. I don't know. I certainly
wouldn't make those claims at this stage.
me tell you a little bit about this tissue and also another feature
of the NIKS cells. A characteristic of our (human) skin is that
the function it has is to die. And our skin is composed of many
layers. And the upper layers of our skin, the layers that produce
almost all the dust in your home, although people don't recognize
this, each of us humans produce about 90 pounds of these skin cells
in the course of our life. So, this skin is called 'renewal tissue.'
And it constantly renews itself. It's a simple tissue but it's very
elegant. And it's elegant because it protects us by the way in which
the cells move and that movement is up from the regenerative layer
of skin which is the first layer through the layers of skin and
then mature skin cells called squamous are destined to fall off,
to be knocked off our bodies by friction, by putting on and off
clothing and so on.
that directionality of cell movement is important because a lot
of things that land on our skin - skin is our largest organ and
its the organ most in contact with the environment - that pathogens
such as viruses, bacteria, chemicals in the environment that land
on our skin - even if they do penetrate our skin and they do, those
cells are destined to fall off our body anyway. So, it's an elegant
plan of nature for this organ to renew itself in that way.
happens when our skin cells mature or go through a process called
'differentiation' is that they will lose the ability to replicate.
In fact, they will totally lose their nucleus. So, that's something
you can see histologically and you can see in a normal skin sample
from you or me. When we cultured the NIKS cells in this organotypic
culturing way which is different from a monolayer tissue culture
in a Petri dish that we were talking about. In organotypic culturing,
the cells are cultured in such a way that they will produce all
the layers of skin, and the NIKS cells will also correctly produce
all the layers of skin. That is the upper mixed cells will mature,
lose their nucleus and fall off.
they can still obey the signals 'to die' when put in the correct
tissue context. So that's why I was so excited!
ABOUT THE HUGE CONCERN OF SO MUCH OF THE POPULATION, ESPECIALLY
IN THE WESTERN INDUSTRIALIZED WORLD, ABOUT WRINKLES AND AGING. ARE
WE TREADING AROUND THE POSSIBILITY THAT THESE CELLS COULD ACTUALLY
BE MADE TO CREATE SKIN THAT WOULD NOT DIE AND WOULD NOT WRINKLE?
I guess I'm treading around it! I'm treading around it because as
an academician I have not focused on that as a use of the cells.
It is a distinct possibility though. It is a distinct possibility.
Another possibility is we don't know, because we haven't done the
experiments yet, whether these cells can produce the appendages
of skin. And what I mean by the appendages of skin is, for example,
a hair. So, that's also another important experiment that we have
not conducted yet to see if that is possible.
YOU WERE SPECULATING ON THE FUTURE FROM WHERE YOU'RE SITTING NOW
AS A LABORATORY EXPERT, HOW LONG DO YOU THINK IT WOULD BE BEFORE
YOU ACTUALLY HAVE COMMERCIAL PRODUCT THAT IS VIABLE IN MEDICINE
AND PHARMACY AND COSMETICS?
is a function of resources. And I think different groups who need
to work together in order to understand the full potential of this
technology. It could move quickly with the correct infusion of resources.
I know at a minimum it will progress along. That's a hard question.
You're asking someone who has a good sized lab at the Univ. of Wisconsin,
but not a cast of hundreds. And who is getting a small private sector
concern established with the aim of furthering development of the
cell line for potential medical application and use in pharmacological
screening. So, we're at the very early stages of this.
THE APPLICATION TO BURN VICTIMS PERHAPS BE ONE OF THE TOP PRIORITIES?
that's certainly a very dramatic example of where there is a need.
Certainly, the tools and products available to physicians are quite
good, but currently there is not an intact skin equivalent that
immediately can be placed on severely burned patients other than
cadaver skin. I can anticipate a question you're going to ask me
about immunological properties of NIKS cells and that's something
we're working on right now.
THEY GO ON TO ANYBODY?
don't know. That would be great. We're working on this and you'll
have to call me up in a year and interview me. I'll give you an
THERE IS NOT AN IMMUNOLOGICAL PROBLEM YOU CAN'T OVERCOME - THEN
THESE CELLS COULD BECOME THE ANSWER TO BURN VICTIMS THROUGHOUT THE
is a distinct possibility."
Info: A new University of Wisconsin-Madison company called Stratatech,
housed at University Research Park, is now pursuing markets for
its patented "immortal human skin." One of its priorities is treatment
for severe burn patients. At least 13,000 people are hospitalized
for burns each year which require extensive skin grafting. Stratatech
hopes to begin human trials of its NIKS skin by 2002. Another
priority is cancer research. Stratatech's Director of Business
Development is UW-Madison oncology professor, Michael Hoffmann,
husband of Dr. Lynn Allen-Hoffmann.
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