Snake venom can be deadly without proper treatment. Interestingly enough, it may also hold the key for treatments against pain, high blood pressure, and cancer according to one analysis. Despite this, scientists still do not understand much about the biology behind the wide range of different snake venoms, which can make it challenging to develop effective treatments in the event of snake bites.
Fortunately, a new study by Dr. Hans Clevers and his team at the Hubrecht Institute in the Netherlands could significantly aid the understanding of snake venom. Dr. Clevers and his team were able to grow miniature snake venom glands using snake stem cells. What’s more remarkable is that these “mini-organs” produced real venom!
In an article posted in Science Magazine, Dr. Clevers talks about how his study was navigating uncharted waters.
“Nobody knew anything about stem cells in snakes. We didn’t know if it was possible at all.”
To produce these “mini-organs”, the researchers removed the stem cells from the venom glands of nine different types of snake and placed them in a mixture of growth factors that contained different hormones and proteins. It turns out that the snake stem cells responded to the same factors used on human and mouse stem cells.
Eventually, the stem cells grew into little clumps of tissue and when the researchers removed the growth factors, they started to change into the same kind of cells that produce venom in the glands of snakes. Additionally, they were able to find that these “mini-organs” expressed similar genes as those observed in real venom glands.
The scientists were even able to test the nature of the “mini-organ” venom as well. A chemical and genetic analysis of the venom revealed that it matched the one made by real snakes. After testing this venom on mouse muscle cells and rat neurons, they also found that it damaged these cells similar to real venom.
The type of toxins and concentration levels can vary drastically in snake venom, even within the same species. This can make developing treatments challenging since they can only be used to combat one type of venom.
Dr. Clevers and his team now plan to study the complexities of venom and venom glands by compiling a “biobank” of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. With the aid of their newly developed “mini-organs”, all of this can be done without the handling of live, dangerous snakes, some of which are rare and difficult to keep in captivity.
Don Reed has been a champion of CIRM even before there was a CIRM. He’s a pioneer in pushing for funding for stem cell research and now he’s working hard to raise awareness about the difference that funding is making.
In a recent article on Daily Kos, Don highlighted one of the less celebrated partners in this research, the humble rat.
A BETTER RAT? Benefit #62 of the California Stem Cell Agency
By Don C. Reed
When I told my wife Gloria I was writing an article about rats, she had several comments, including: “Oo, ugh!” and also “That’s disgusting!”
Obviously, there are problems with rats, such as
when they chew through electrical wires, which may cause a short circuit
and burn down the house. Also, they are blamed for carrying diseased
fleas in their ears and spreading the Black Plague, which in 1340 killed
half of China and one-third of Europe—but this is not certain. The
plague may in fact have been transmitted by human-carried parasites.
But there are positive aspects to rats as well. For
instance: “…a rat paired with another that has a disability…will be
very kind to the other rat. Usually, help is offered with food,
cleaning, and general care.”—GUIDE TO THE RAT, by Ginger Cardinal.
Above all, anyone who has ever been sick owes a
debt to rats, specifically the Norway rat with that spectacular name,
rattus norvegicus domesticus, found in labs around the world.
I first realized its importance on March 1, 2002,
when I held in my hand a rat which had been paralyzed, but then
recovered the use of its limbs.
The rat’s name was Fighter, and she had been given a derivative of embryonic stem cells, which restored function to her limbs. (This was the famous stem cell therapy begun by Hans Keirstead with a Roman Reed grant, developed by Geron, and later by CIRM and Asterias, which later benefited humans.)
As I felt the tiny muscles struggling to be free,
it was like touching tomorrow— while my paralyzed son, Roman Reed, sat
in his wheelchair just a few feet away.
Was it different working with rats instead of mice? I had heard that the far smaller lab mice were more “bitey” than rats.
Wanting to know more about the possibilities of a “better rat”, I went to the CIRM website, (www.cirm.ca.gov) hunted up the “Tools and Technology III” section, and the following complicated sentence::
“Embryonic stem cell- based generation of rat models for assessing human cellular therapies.”
Hmm. With science writing, it always takes me a
couple of readings to know what they were talking about. But I
recognized some of the words, so that was a start.
“Stemcells… rat models… human therapies….”
I called up Dr. Qilong Ying, Principle Investigator (PI) of the study.
As he began to talk, I felt a “click” of recognition, as if, like pieces of a puzzle, facts were fitting together.
It reminded me of Jacques Cousteau, the great
underwater explorer, when he tried to invent a way to breathe
underwater. He had the compressed air tank, and a mouthpiece that would
release air—but it came in a rush, not normal breathing.
So he visited his friend, race car mechanic Emil
Gagnan, and told him, “I need something that will give me air, but only
when I inhale,”– and Gagnan said: “Like that?” and pointed to a metal
contraption on a nearby table.
It was something invented for cars. But by adding
it to what Cousteau already had, the Cousteau-Gagnan SCUBA (Self
Contained Underwater Breathing Apparatus) gear was born—and the ocean
could now be explored.
Qi-Long Ying’s contribution to science may also be a piece of the puzzle of cure…
A long-term collaboration with Dr. Austin Smith centered on an attempt to do with rats what had done with mice.
In 2007, the Nobel Prize in Medicine had been won by Dr. Martin Evans, Mario Capecchi, and Oliver Smithies. Working independently, they developed “knock-out” and “knock-in” mice, meaning to take out a gene, or put one in.
But could they do the same with rats?
“We and others worked very, very hard, and got nowhere,” said Dr. Evans.
Why was this important?
Many human diseases cannot be mimicked in the
mouse—but might be in the rat. This is for several reasons: the rat is
about ten times larger; its internal workings are closer to those of a
human; and the rat is considered several million years closer (in
evolutionary terms) to humans than the mouse.
In 2008 (“in China, that is the year of the rat,” noted Dr. Ying in our conversation) he received the first of three grants from CIRM.
“We proposed to use the classical embryonic stem
cell-based gene-targeting technology to generate rat models mimicking
human heart failure, diabetes and neurodegenerative diseases…”
How did he do?
In 2010, Science Magazine honored him with
inclusion in their “Top 10 Breakthroughs for using embryonic stem
cell-based gene targeting to produce the world’s first knockout rats,
modified to lack one or more genes…”
And in 2016, he and Dr. Smith received the McEwen Award for Innovation, the highest honor bestowed by the International Society for Stem Cell Research (ISSCR).
Using knowledge learned from the new (and more
relevant to humans) lab rat, it may be possible to develop methods for
the expansion of stem cells directly inside the patient’s own bone
marrow. Stem cells derived in this fashion would be far less likely to
be rejected by the patient. To paraphrase Abraham Lincoln, they would
be “of the patient, by the patient and for the patient—and shall not
perish from the patient”—sorry!
Several of the rats generated in Ying’s lab (to mimic human diseases) were so successful that they have been donated to the Rat Research Resource center so that other scientists can use them for their study.
“Maybe in the future we will develop a cure for some diseases because of knowledge from using rat models,” said Ying. “I think it’s very possible. So we want more researchers from USC and beyond to come and use this technology.”
This is the time of year when everyone puts out their lists of the best and worst of the last 12 months. The best movies (”Guardians of the Galaxy”, “The Grand Budapest Hotel”) the worst movies (“Guardians of the Galaxy”, “The Grand Budapest Hotel” – it’s all a matter of taste really) the best music etc. You get the picture.
So it’s always fun to see what makes the list of the “biggest scientific breakthroughs” of 2014. I put those in quotations because I always get a little nervous using the word “breakthrough” when talking about stem cells; what seems like a breakthrough one year, could prove out to be a dud the next. Or, worse still, a fake – see yesterday’s blog. But when Science magazine uses the word as part of its article: ‘Breakthrough of the Year: The top 10 scientific achievements of 2014’, I think it has a shot at being accurate.
The list is compiled by the editors of Science, to highlight what they call “a singular scientific achievement”. I’ll tell you what they chose as the winner in a moment, but there are two stem cell stories that were listed as runners-up.
Giving new life to old mice; cartoon courtesy of
The first story was about a trio of studies that showed how giving older mice the blood of younger mice can help rejuvenate them in surprising ways, including improving muscle and brain function. We blogged about this work when it came out in May. It’s already being tested to see if it might work in people, with 18 Alzheimer’s patients getting injections of plasma donated by young adults, to see if that can help slow down or halt the progression of the disease.
The second story was about work turning embryonic stem (ES) cells into mature beta cells, the kind of cells found in our pancreas that help produce insulin. These are also the cells that are destroyed in type 1 diabetes. This year researchers found a way to turn ES cells into mass quantities of beta cells, a critical first step in developing a therapy for type 1 diabetes. The next step is to find a way to protect those cells from the same autoimmune reaction that killed the beta cells in the first place.
What’s particular interesting about this work – at least from our perspective – is that we are funding a clinical trial run by ViaCyte that uses this same approach, and has the cells encapsulated in a special device to protect them from the immune system.
Getting two stem cell stories on the list of the biggest scientific stories of the year is no mean achievement, and a sign of the progress the field is making. We’re hoping that 2015 sees even more stem cell stories making positive news headlines.
As for the story named the “Breakthrough of the Year”, it was the ten-year mission that ended with the landing of a spacecraft on a comet 326 million miles away from earth. Coming second to that kind of astonishing achievement is no disgrace.