Tag Archives: nobel prize

Reprogrammed frog and mouse cells win the 2012 Nobel Prize

This morning the Nobel Assembly announced that the 2012 Nobel Prize in Physiology or Medicine will be shared by John B. Gurdon and Shinya Yamanaka for their “discovery that mature cells can be reprogrammed to become pluripotent”.  Animal research played a key role in the research honoured by the prize, specifically the studies of frogs undertaken by Professor Gurdon and studies of mice performed by Professor Yamanaka.

Sir John Gurdon. Image: Nobel foundation.

Professor Gurdon’s key work showed in a series of studies undertaken at the University of Oxford in the late 1950’s and 1960’s that if the nucleus of a specialised cell from a frog of the species Xenopus laevis - initially from late embryonic cells and subsequently adult intestinal and skin cells – was transferred into an egg whose nucleus had been removed, it could give rise to normal frog that could themselves produce offspring. This demonstrated for the first time that the nucleus of an adult cell is totipotent, and that in under certain conditions it could give rise to all cell types, including eggs and sperm, that are required in a healthy adult.

The very first Xenopus frog produced by somatic nuclear transfer to reach sexual maturity. Image: J.B. Gurdon

In 2009 Sir John wrote an account of his research on nuclear transfer in Xenopus for Nature Medicine, which can be read online without subscription, after he and Professor Yamanaka were presented with the  Albert Lasker Basic Medical Research Award in 2009.

Professor Shinya Yamanaka. Image: Nobel foundation

Almost 4 decades later Professor Yamanaka, then at the Kyoto University Institute for Frontier Medical Sciences, made another great step forward by proving that it was possible to transform adult mouse cells into a pluripotent stem cells without nuclear transfer. By inserting 4 genes whose expression is associated with the embryonic state into the adult cell, his team were able to create the first induced pluripotent stem (iPS) cells, cells that could give rise to any tissue in the body.

Earlier this year in a post congratulating Professor Yamanaka’s on winning the 2012 Millenium Technology Prize I noted that:

The work briefly described above was a technological tour-de-force where Prof. Yamanaka and his colleagues selected 24 genes which had previously been identified as having key roles in mouse embryonic stem cells, and developed a screening method using skin fibroblast cells derived from mice that had be genetically modified with an antibiotic resistance gene that was only expressed in embryonic cells, so that only cells that were in an embryonic state would survive in a culture containing the antibiotic. Different combinations of these 24 genes were screened for their ability to induce to the production of colonies of embryonic -like cells from adult fibroblasts.  They eventually identified just 4 genes – Oct3/, Sox2, Klf4 and c-Myc – that together could reprogram adult mouse fibroblast cells to a pluripotent embryonic-like state (1), and subsequently demonstrated that these iPS cells could give rise to a wide variety of  tissue types when incorporated into mice, either by subcutaneous injection into adult mice or incorporation into early mouse embryos. By modifying their method slightly to also include expression of an important developmental gene named Nanog  they were then able to generate chimeric mice (mice whose tissues are made up of a mixture of cells derived from their own embryonic stem cells, and cells derived from iPS cells) which were capable of transmitting the iPS cells to the next generation of mice (2).

Soon after this Prof. Yamanaka succeeded in generating iPS cells from human fibroblasts, using the same techniques used for the mouse cells, and a whole new and exciting field of biomedical research was born.

1)      Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell 2006 Vol. 126(4):663-76. PubMed: 16904174

2)      Okita K., Ichisaka T., Yamanaka S. “Generation of germline-competent induced pluripotent stem cells.” Nature Vol. 448:313-317 (2007). PubMed:17554338””

It’s worth remembering that this breakthrough did not come out of thin air, and built on years of research that followed the pioneering work of Martin Evans and Gail Martin who demonstrated that cells derived from mouse embryos could be cultured and give rise to all tissue types…the first embryonic stem cells.

The field of iPS cell research has progressed swiftly since the first mouse iPS cells were produced just 6 years ago, and the techniques used to produce the cells have been refined to address early concerns that the inserted genes might give rise to tumors, but as Prof Yamanaka outlined in a recent review of progress in the field there is still a lot of scope for improvement.  Nevertheless iPS cells are already showing promise in a variety of medical research applications – for example to create nerve cell lines from Parkinson’s disease patients in order to study the processes that trigger the degeneration, or  to evaluate the toxicity of new drugs – and are expected to join  human embryonic stem cells as key components of regenerative medicine.

This year’s Nobel Prize in Physiology or Medicine highlights once again the key role played by animal research in making groundbreaking discoveries that give rise to new fields of medicine, and we offer our heart-felt congratulations to John Gurdon and Shinya Yamanaka.

 

Addendum: In a statement to Reuters on the problem of the unproven stem cell therapies being offered for a myriad of disorders by private health clinics around the world - and widely touted on the internet -Professor Yamanaka highlighted the key role played by animal research in ensuring that real stem cell therapies are safe and effective:

Yamanaka, who shared the Nobel Prize for Medicine on Monday with John Gurdon of the Gurdon Institute in Cambridge, Britain, called for caution [on stem cell therapies - PB].

“This type of practice is an enormous problem, it is a threat. Many so-called stem cell therapies are being conducted without any data using animals, preclinical safety checks,” said Yamanaka of Kyoto University in Japan.

“Patients should understand that if there are no preclinical data in the efficiency and safety of the procedure that he or she is undergoing … it could be very dangerous,” he told Reuters in a telephone interview.

Yamanaka and Gurdon shared the Nobel Prize for the discovery that adult cells can be transformed back into embryo-like stem cells that may one day regrow tissue in damaged brains, hearts or other organs.

“I hope patients and lay people can understand there are two kinds of stem cell therapies. One is what we are trying to establish. It is solely based on scientific data. We have been conducting preclinical work, experiments with animals, like rats and monkeys,” Yamanaka said.”

 

Paul Browne

 

 

 

The new face of transplant surgery, thanks to animal research

Yesterday the University of Maryland Medical Center (UMM) announced most extensive full face transplant completed to date, including both jaws, teeth, and tongue. In a marathon 36-hour operation the surgical team led by Professor Eduardo Rodriguez were able to transplant a face of an anonymous donor onto their patient Richard Lee Norris, who had been injured in a gun accident 15 years ago.  The operation was the culmination of years of clinical and animal research undertaken at UMM under the leadership of Professor Stephen Bartlett, and funded by the Department of Defense and  Office of Naval Research due to its potential to help war veterans who have received serious facial injuries.

This successful operation, termed a vascularized composite allograft, was made possible not only by the selflessness of the family of the anonymous donor, but also by the years of animal research undertaken by Professors Rodriguez and Bartlett and colleagues. For example, a key factor in the success of this operation was that they transplanted high amounts of vascularized bone marrow (VBM), which came inside the transplanted jaw, a technique that was developed by the team after observing that tissue rejection following composite tissue allotransplantation in a cynomolgus monkeys was greatly reduced when VBM was included in the transplant. This discovery will also help to reduce the amount of immunosuppression that Mr. Norris and future patients require following facial transplants.

Of course this is far from the first contribution that animal research has made to transplant surgery, from the development of the techniques of kidney transplant through research in dogs by Joseph Murray and colleagues, to the careful experiments in dogs conducted by Norman Schumway and Richard Lower that led to the first successful heart transplants, to the studies in mice and rats that identified the immunosuppressive properties of the drug cyclosporin that transformed the transplantation field in the 1980′s, animal research has made a crucial contribution to this field. Indeed, in his 1990 Nobel Lecture Edward Donnall Thomas stressed the importance of animal research to his Nobel prize winning discoveries concerning bone marrow transplantation.

Finally, it should be noted that marrow grafting could not have reached clinical application without animal research, first in inbred rodents and then in outbred species, particularly the dog.”

Animal research continues to make key contributions to transplant science, and we have had several opportunities to discuss its role in the development of lab-engineered tissues for transplant, such as the artificial trachea and bladder, on this blog.

Yesterday’s news from the University of Maryland is another reminder that animal research is still crucial to advances in transplant surgery. It is also worth remembering that when animal rights groups attack animal research conducted by the Department of Defense, it is work such as that which led to yesterday’s breakthrough that they are attacking.

Paul Browne

Of Mice, Rice, Flies and Men

Animal rights activists often argue that animal models are irrelevant for human medicine, because they are ‘so different’ from us. But in fact some basics are shared across wildly distant species – something that the Nobel Committee acknowledged last year when they gave the Prize for Medicine and Physiology to Bruce Beutler and Jules Hoffmann for discovering the ‘early warning’ signals that set off immune responses in flies, mice and humans.

On Jan. 25 both Beutler, who works at the University of Texas in Dallas, and Hoffmann of the University of Strabourg, France, were at the University of California, Davis talking to a packed house about their work. Joining them on stage was UC Davis plant pathologist Pam Ronald, who studies rice, and Luke O’Neill of Trinity College Dublin, Ireland, who talked about human medicine.

(Watch the presentations here: http://ccm.ucdavis.edu/immunity.html)

L to R symposium speakers Bruce Beutler, Jules Hoffmann, Luke O'Neill and Pamela Ronald, with (far right) symposium sponsor Murray Gardner.

Work in these very different organisms can give insights that advances human medicine. From the basic discoveries in mice, flies and even rice could come new drugs and new approaches to treat heart disease, rheumatoid arthritis, inflammatory bowel disease and other conditions.

Our immune system has two lines of defense. The innate immune system reacts first, attacking invading microbes and triggering inflammation. If that response fails, the adaptive immune system fights back with antibodies and specialized killer cells. Afterward, the adaptive immune system retains a memory that allows a more rapid and powerful response if the same virus, bacterium or parasite comes back.

Only animals with backbones, from fish to humans, have an adaptive immune system. But all animals, including insects, as well as plants, have innate immune systems.

In the 1990s, Ronald (working with rice), Hoffmann (with Drosophila flies) and Beutler (with mice) identified genes for immune receptors that triggered innate immunity in the rice, flies and mice, and found that the genes were remarkably similar despite hundreds of millions of years of evolution.

From this common trigger, plants, insects and animals develop different types of response to invaders.

Activation of the immune system is not always a good thing. It can lead to allergy, inflammatory diseases such as rheumatoid arthritis or autoimmunity, when the body starts attacking its own tissues.

In his talk, for example, Beutler described how his team, working with mice, has isolated genes related to inflammatory bowel disease, while O’Neill talked about the possibility of being able to develop drugs to treat a wide range of diseases linked to inflammation.

The symposium is an annual event sponsored by a fund created by AIDS pioneer and UC Davis professor emeritus Murray Gardner, who previewed in an interview for Sacramento Public Radio Jan. 24 [http://www.capradio.org/168919] At the beginning of the AIDS epidemic in the 1980s, Gardner helped discover viruses similar to HIV in monkeys and cats – animal models that have been of vital importance in discovering drugs to treat and prevent HIV/AIDS.

– Andy Fell

From Science to Miracle in 2 years: The Discovery of Insulin

A mere one hundred years ago, when people were diagnosed with diabetes, they were handed down a death sentence.  There was no treatment for the disease.  Children would become skeletons and die of severe weight loss in front of their families.

The first breakthrough in the search for a treatment came in 1879 with the discovery by Von Mering and Minkowski that removing the pancreas in dogs led them to develop all the symptoms of diabetes and die shortly after.  They proposed that the pancreas was involved in the metabolism of sugars.

In 1921, Banting and Best replicated this earlier result and took it a step further – working under the supervision of Macleod they showed that they could restore diabetic dogs to their normal state by injections of an extract of produced by the Islets of Langerhans obtained from healthy dogs.

With this result in a dog model of diabetes they subsequently recruited Dr. Collip, a biochemist, they who helped them extract a reasonably pure formula of insulin from the pancreas of cattle. This painstaking process of refinement of the technique for extracting insulin required many tests in rabbits in order to evaluate the potency and safety of the insulin preparations.

In January, 1922, the first human patient, a diabetic teenager named Leonard Thompson, became the first person to receive an injection of insulin. The improvement was so astonishing, nearly miraculous, that the news about this medical breakthrough traveled the world within days.

An early patient: before and four months after treatment with insulin.

The University of Toronto gave pharmaceutical companies license to produce insulin free of royalties (would this count as an argument against the notion that universities merely seeking financial gain for their work?).  In early 1923, just one year after the first test injection, insulin became widely available and has saved countless human lives since.  Banting and Macleod received the Nobel Prize in Medicine for their work.

This is only one of multiple stories about how animal research has benefited mankind.  This is research that will benefit you, your children, and all future generations.  An honest discussion of the use of animals in scientific research must acknowledge these facts, how we arrived at them, and recognize that despite the difficult ethical decision to use dogs in the discovery of insulin, today millions of humans are alive thank to the work of scientists engaged in biomedical research.

Dario Ringach

Bob Edwards wins 2010 Nobel Prize for developing IVF: Thank the mice, rabbits, hamsters…

Professor Robert G. Edwards of the University of Cambridge has long been recognized as one of the pioneers of reproductive medicine. His most famous accomplishment, along with surgeon Patrick Steptoe*, came in 1978 with the birth of Louise Joy Brown, the first baby born through in-vitro fertilization.  This achievement has now been recognized by the Nobel Assembly who awarded him the Nobel Prize in Physiology or Medicine 2010 for “the development of in vitro fertilization”.

As Dario discussed in an article for this blog a few months ago the development of IVF by Bob Edwards depended on basic and applied research undertaken in rabbits and hamsters by pioneers including Gregory Pincus and Min Chueh Chang, who identified the essential conditions required for IVF.

In advanced information accompanying today’s announcement the Nobel Assembly notes the importance of this research in laying the foundations for the development of human IVF by Bob Edwards and Patrick Steptoe, and also discusses how Bob Edwards’ own extensive research on the reproductive biology of mice – and animal research he and his colleagues conducted in a variety of species while working on IVF – aided progress. In particular the Nobel Assembly highlights how his experience with mice in enabled Bob Edwards to solve a critical problem that was preventing successful IVF, by developing a way to harvest human egg cells at the optimal stage of their maturation prior to in vitro fertilization.

Professor Robert Edwards, Nobel Laureate and IVF pioneer

Without the decades of careful animal research undertaken by Bob Edwards, Gregory Pincus, Min Chueh Chang, and scores of their colleagues it is unlikely that IVF would ever have become a reality.

We heartily congratulate Professor Edwards on his Nobel Prize, an award that recognizes his outstanding contribution to a medical advance that has brought joy to hundreds of thousands of families around the world.

* Sadly Patrick Steptoe died in 1988 and therefore could not share the Nobel Prize with Robert Edwards.

Paul Browne

Herceptin: When personalized medicine and animal research meet.

Personalized medicine is very popular among medical researchers these days, and it’s not hard to see why. By tailoring treatment to fit an individual patient, for example by using information about their genetic makeup, scientists hope to make treatments more effective while at the same time avoiding or minimizing adverse effects.

Anti-vivisectionist Dr. Greek writes about personalized medicine as if one could do this work without relying on animal research at all.

For example, he writes:

When will personalized medicine become a reality?

We are already seeing it, with breast cancer being a prime example. Breast cancer treatment is now determined in part based on a patient’s genetic makeup. About 25-30 percent of breast cancer patients overexpress the HER2 oncogene, which is a gene involved in the development of cancer. The overexpression results in an increase in the replication of the cancer cells. Physicians are now able to identify which breast cancer patients overexpress HER2 and give them Herceptin, a monoclonal antibody that inhibits HER2

This is true…  but where did Herceptin come from?   Does he know?

Herceptin, a humanized mouse monoclonal antibody. Image courtesy of Andrey Ryzhkov.

The basic research that led to the development of Herceptin (Trastuzumab) goes back to work by Milstein and Kohler who discovered the potential for using antibodies to fight disease.    They developed the first methods to produce monoclonal antibodies using mice.   Both Milstein and Kohler went on to win the Nobel Prize partly for this work.

Harold Varmus (now back as Director of the National Cancer Institute) showed that disturbances in some gene families could turn the cells cancerous.  He also went on to win the Nobel Prize for this work.  Robert Weinberg subsequently discovered in rats that a mutant gene (named “neu”) encoding a tyrosine kinase promoted cancer features in cells, contributing to the development of neuroglioblastoma tumors.

Later, Axel Ullrich and collaborators at Genentech cloned the human HER2/neu gene.  Work at UCLA Dennis Slamon and colleagues showed HER2 over-expression in 25% of patients with aggressive breast cancer.

Through screening studies on monoclonal antibody candidates in vivo in mice implanted with HER-2 positive human tumors the group at Genentech then developed the mouse 4D5 (parent of Herceptin) and showed that 4D5 could suppress the growth of HER2 tumor cells as well as enhance the ability of the host immune system to kill them.   A collaboration between UCLA and Genentech then demonstrated that radio-labeled 4D5 localized to HER2-expressing tumors in both mice and human patients.

With the information obtained from animal experiments, Genentech created Herceptin by humanizing the 4D5 mouse antibody directed at HER2.   The ability of Herceptin to prevent tumor growth was then assessed in mice implanted with HER-2 positive human tumor xenografts, and the concentration of Herceptin required in the blood to achieve anti-tumor activity was determined before starting human clinical trials.

So, you see…  Herceptin was derived from a mouse antibody.

Let me repeat: a mouse antibody!

Clinical trials in humans subsequently showed the effectiveness of Herceptin to treat HER2 positive breast cancer.

Perhaps, Dr. Greek and other animal rights activists should carefully listen to the experts that were actually involved in the process of developing Herceptin (a drug he appears to thinks highly of) which, indeed, benefits so many women battling breast cancer.   A drug derived from mice, and developed in mice.

Here is what Robert Weinberg had to say about Dr. Greek’s views on research:

Dr. Greek says the silliest things, [...] implying that people are not studying human tumors, and implying that the kinds of experiments that one can do in mice can be done as well in humans — truly mindless!

I couldn’t have said it better.

Dario Ringach

Laying the foundations of medical research

For the past couple of weeks a debate has been raging on the Opposing Views website between Speaking of Research’s Dario Ringach and the anti-vivisectionist Ray Greek. It has been a debate shaped by Dr. Greek’s attempts to persuade readers to agree with his very narrow concept of what prediction means in biology and his frankly impoverished view on the role of basic research in advancing medical science, and to oblige those debating them to accept a playing field rigged to set them at a disadvantage.  Judging by Dario’s most recent opinion piece and an article written a couple of days ago on the role of basic research Dr. Greek failed in this attempt.

British biochemist Sir Tim Hunt, who won the Nobel Prize for medicine in 2001.

Among all the discussion was one comment that directed readers to an excellent example of the value of basic research and the how study of animal models made many key discoveries possible. Earlier this week the BBC aired a program in their Beautiful Minds series featuring Sir Tim Hunt, who was awarded the Nobel Prize in 2001 for his research on how the cell cycle – through which cells grow and divide – is controlled.  Sir Tim’s work focused on the role of a family of proteins known as cyclins and as the Beautiful Minds program explains the initial breakthrough came from studies of the fluctuations in the pattern of protein expression during the cell cycle in sea urchin eggs.  This discovery was followed swiftly by the demonstration that cyclins were also present in yeast, clams and frogs, allowing Sir Tim and his colleagues to predict that they would have a role in regulating the cell cycle in many species,  including humans, a prediction that was soon confirmed to be true (1).

This program is a reminder that while discussion of animal research tends to focus on animals such as mice, rats and monkeys a lot is being learned about the fundamentals of our physiology through research on more humble model organisms, a diverse collection that includes not just sea urchins and clams but also nematode worms and flies .  These animals, along with other model organisms such as yeast and bacteria, enable us to study how living things work at a very fundamental level, laying the theoretical foundations for future applied and translational research that yields innovative treatments for disease and injury. At the same time, researchers studying other aspects of physiology often require higher mammals. The study of complex brain functions, including vision, hearing, memory, attention and motor planning, as well as how these functions fail in diseases of the central nervous system, is a prime example of this.

If you haven’t watched the Beautiful Minds series yet I strongly urge you to do so, the programs provide a fascinating (if not always flattering) insight into how science works.  And don’t delay: they are only available to view on the BBC iPlayer for another 7 days!

Paul Browne

1)      Pines J.  and Hunter T. “Isolation of a human cyclin cDNA: evidence for cyclin mRNA and protein regulation in the cell cycle and for interaction with p34cdc2.” Cell Volume 58(5), Pages 833-846 (1989)  PubMed: 2570636