Tag Archives: frog

Research Roundup: Killing cancer cells, growing drugs in chicken eggs and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Growing drugs in chicken eggs may lower their cost. Interferon beta is a cell-signaling protein found in the body that acts against viruses, and is used to treat various illnesses ranging from multiple sclerosis to cancer. The downside is that the interferon protein molecule is extremely expensive to manufacture, costing between $300-$1000 for one microgram. Most dosages start at several micrograms; to treat multiple sclerosis, for example, the starting dose is 30 micrograms. Researchers developed a novel way to mass produce interferon beta using chickens genetically modified using CRISPR technology. While investigators still need to show that the chicken-produced protein is structurally the same as the protein in current medications, this technique could reduce the price of cancer drugs by at least 90%. Additionally, a drug produced using modified chickens, called Kanuma, has already been approved by the US Food and Drug Administration to treat Lysosomal Acid Lipase Deficiency. Researchers are currently writing up their results for publication.
  • How Studying Frog Embryos Is Helping Advance Tissue Engineering By Leaps And Bounds. The embryos and tadpoles of Xenopus frogs are transparent allowing researchers to observe their internal anatomy during development. This, and other features like their tolerance to extensive manipulation, make them easy to work with in a research setting. Frogs and humans have many similarities genetically and physiologically. Researchers at the University of Pittsburgh are working with frog embryos to understand the mechanical processes that guide the development of a complete living organism. They hope to use this to develop a tool that tissue engineers can use in regenerative medicine when building new tissue. Dr. Lance Davidson, professor at the University’s Swanson School of Engineering explains, “Many engineering fields have some kind of software or simulation tool that can take the guesswork out their designs before they actually start building. We are developing something similar for tissue engineers so they don’t have to rely on trial and error all the time.” They hope to apply this to support regenerative medicine therapies. Original source: Pitt’s Swanson School of Engineering

  • Engineered Proteins lower body weight in obese mice, rats, and primates. Obesity is an increasingly common problem throughout the world. Surgeries such as gastric bypass or sleeve are quite effective, however the procedure is highly invasive and can lead to permanent negative side effects. Because of these negative side effects, scientists are currently exploring what different types of proteins our bodies secrete during metabolism. One promising protein that they identified was growth differentiation factor 15 (GDF15). By treating obese mice with GDF15, scientists discovered that mice reduced how much food they were eating leading to a reduction in body weight, and had healthier metabolism. They then tested this treatment in obese rats and cynomolgus monkeys, and found the same results. Through more intensive tests they also discovered that treatment with GDF15 delays gastric emptying, changed food preferences, and activated areas of the gut-brain axis. This work is a great example of scientific discoveries following the path of mouse to rat to non-human primate and, hopefully one day soon, human. This research was published this week in Science Translational Medicine.
  • Zebrafish research guides new therapy possibilities for rare genetic disorder. Alagille Syndrome is a rare (1 in 100,000 births), potentially life-threatening genetic disorder that affects the heart, liver, and kidneys among other body systems. New research using zebrafish has helped to identify the tissues and genes which are important to the development of liver duct cells, and how the mutation associated with Alagille Syndrome causes development to go awry. The team, based out of Sanford Burnham Prebys Medical Discovery Institute, hopes that this discovery will aid in the development of regenerative therapies that will restore liver function, and possibly prevent the need for liver transplant in certain patients with this disorder. This research was published in Nature Communications.

Zebrafish: Wellcome Trust Sanger Institute

  • New compound targets energy generation killing cancer cells. Sperm cells can generate energy and they can do so in harsh conditions because they strategically contain mitochondria in their “head”. Cancer cells, can also survive under harsh conditions, and they can adapt to a shortage of nutrients by reprogramming the energy generation system. Cancer cells, in contrast to normal cells, contain an enzyme called FerT — and unsurprisingly — the only other cell containing this enzyme is sperm. Researchers hypothesized that by disrupting the activity of FerT in cancer cells – they would starve cancer cells of energy and that they would die. To this end – they created a synthetic orally administered compound (E260), and found in mouse cancer model – that indeed, cancer cells are killed. They also check other normal cells and found them to be unaffected. This research was published in the journal Nature Communications.

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

 

 

 

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