Monthly Archives: October 2017

FASEB report makes recommendations for animal research regulations

On October 24, a group of professional scientific organizations released a set of groundbreaking recommendations entitled, “Reforming Animal Research Regulations: Workshop Recommendations to Reduce Regulatory Burden.” This report is the result of an April 17, 2017 workshop organized by the organizations: The Federation of American Societies for Experimental Biology (FASEB), the Association of American Medical Colleges (AAMC), and the Council on Governmental Relations (COGR), with assistance from the National Association for Biomedical Research (NABR). The goal of the April workshop was “to provide actionable recommendations for promoting regulatory efficiency, animal welfare, and sound science.

The workshop was convened, in part, in response to the 2016 passage of the 21st Century Cures Act (Cures), which directs leadership of the National Institutes of Health (NIH), the United States Department of Agriculture (USDA), and the Food and Drug Administration (FDA) to “complete a review of applicable regulations and policies for the care and use of laboratory animals and make revisions, as appropriate, to reduce administrative burden on investigators while maintaining the integrity and credibility of research findings and protection of research animals” within two years of the bill’s enactment (which occurred on December 13, 2016).

The recommendations in the report are directed to federal agencies that are involved in the oversight of federally funded animal research, particularly the NIH and the USDA. The recommendations stem from the workshop’s identification of requirements that demand significant administrative effort without demonstrating enhanced animal welfare. Thus, the recommendations consist of steps that agencies and Congress can take to reduce these inefficiencies.

A Veterinary Technician works with rodents

The aim of the report is to find ways of maintaining animal welfare while reducing administration

Speaking or Research applauds the thorough and thoughtful process of deliberation this group of organizations went through, as well as the transparency provided in the report. We believe that such transparency will allow for a public discussion of the system and of the potential for improvement. Here, we provide a high-level summary of the recommendations. The full report and set of recommendations are freely available at FASEB’s website.

The Major Recommendations are geared toward several major governing and oversight bodies: 1) The Executive Office of the President and Congress, 2) Both the NIH and USDA, and 3) the NIH and USDA separately.

1. Recommendations to The Executive Office of the President and Congress

The Executive Office of the President (EOP) and the Office of Management and Budget (OMB) should consolidate animal research oversight under a single Federal office or entity with one primary set of regulations and guidance documents. A committee of experts engaged in animal research, comprised of institutional administrators, Institutional Animal Care and Use Committee (IACUC) members, investigators, and veterinarians, should be invited to assist with this consolidation effort.

The EOP and OMB should require at least a 60-day comment period on the merits and impact of any proposed policies, guidance documents, frequently asked questions (FAQs), or interpretive rules before they are issued. Final policies and guidance should reflect germane comments received from the regulated community.

Congress should amend part of the Animal Welfare Act (AWA) to require only annual inspection by the IACUC, and should revise the requirement for annual USDA inspection.

2. Recommendations to both the NIH and the USDA

Appoint an external advisory group of experts engaged in animal research, from entities that receive federal research funding, to serve as advisors. The advisory group should include institutional administrators, IACUC members, veterinarians, and investigators engaged in animal research.

Have all Public Health Service (PHS) and USDA regulations, policies, guidance documents, FAQs, and interpretive rules, as well as the process for generating them, reviewed by an external advisory group of the very experts engaged in animal research (from entities receiving federal funding). As above, this group should consist of institutional administrators, IACUC members, veterinarians, and investigators engaged in animal research. This review will ensure that the documents emphasize matters of core importance to animal welfare identified in the regulatory language, and that they are consistent with current scientific and technological knowledge and approaches.

Establish a risk-based process for review of animal research protocols, similar to that which is used for human subjects research. Through a Notice in the Federal Register, NIH and USDA could amend the protocol review requirement to define types of studies that are low-risk, noninvasive, or minimally invasive. These studies could then be subject to less stringent review criteria than higher-risk, more invasive studies.

3a.    Recommendations to NIH

Use the Guide for the Care and Use of Laboratory Animals (Guide) as it was intended – as a guide, not as a regulatory document. IACUC-approved strategies stemming from recommendations in the Guide should not be not be required to be included in semiannual reports to the Institutional Official.

Eliminate the requirement for verification of protocol and grant congruency in the NIH Grants Policy, so as to allow for reasonable advances, discoveries, and other developments in overall research objectives.

Revise NIH guidance regarding prompt reporting to include only those incidents that jeopardize the health or well-being of animals.

Streamline the assurance for animal research. For Category 1 institutions, allow proof of accreditation in lieu of the detailed program description.

3b.   Recommendations to USDA

Revise the relevant section of the AWA to specify IACUC reviews of animal research protocols at least once every three years, and at appropriate intervals as determined by the IACUC. This modification would make review frequency consistent with PHS Policy.

Revise the USDA Animal Care Policy #14 to reflect the language that exists in the AWA and the AWA Regulations (AWR), so that multiple survival operative procedures may be allowed at the discretion of the IACUC and as justified for scientific and animal welfare reasons. This modification will aid the research community in reducing the number of animals involved in research.

Align language in the USDA Animal Care Policy #12 with respect to literature searches with language in the AWR that charges the IACUC to determine “that the principal investigator has considered alternatives to procedures that may cause more than momentary or slight pain or distress to the animals, and has provided a written narrative description of the methods and sources…”

We urge people to read the report and come to their own conclusions. If you have any thoughts on the recommendations made, please do share them in the comment section.

Of Mice and Mammaries, Part 4: From animal models to human therapies

In light of Breast Cancer Awareness Month, Justin Varholick traces how mice have helped breast cancer research over the past century. Over the past month, in Parts 1, 2, and 3 of this series, he discussed how scientists began studying mammary tumors in mice and how they have advanced their study to better understand human breast cancer. In the fourth post of this series, he looks at how a hormonal therapy was discovered and how scientists are paving a way for new and effective discoveries in patient derived xenografts.

Breast cancer comes in many forms and can be detected at different stages throughout a women’s life. After a doctor diagnoses the type of breast cancer, they can suggest surgery and/or therapies. Surgery is the common practice to remove breast tumors and is also referred to as lumpectomy (breast-conserving surgery) or mastectomy (whole breast removal); and may also involve removal of lymph nodes. Doctors will then advise their patients to have radiation therapy, chemotherapy, hormonal therapy, or targeted therapy – this is to assure that the breast cancer does not return.

Types of Breast Cancer Surgery Therapies
Invasive Breast Cancer (stages I-IV) Lumpectomy or Mastectomy depending on stage Radiation along with chemo or other drug therapies
Ductal Carcinoma in situ Lumpectomy or Mastectomy depending on degree Hormone therapy for 5 years
Lobular carcinoma in situ No surgery May consider hormone therapy
Inflammatory breast cancer Mastectomy Chemo before and radiation after surgery
Breast cancer during pregnancy Lumpectomy or Mastectomy Any therapy after delivery
Triple-negative breast cancer Mastectomy Chemotherapy may be useful

(Information from American Cancer Society)

Because chemotherapy and radiation therapy are common methods used to treat many different types of cancers post- and pre-surgery, we will focus on the most widely used therapy that specifically targets breast tumors – Tamoxifen.

History of Tamoxifen, a targeted hormonal therapy

The history of Tamoxifen begins around the same time the first mammary tumors in mice were discovered. In 1896, pioneering cancer surgeon Dr. George Beatson discovered that he could extend the lives of breast cancer patients by surgically removing their ovaries. This surgery was then replicated in mice in 1916. The reason the removal of ovaries helped breast cancer patients was because ovaries are major sources for producing the hormone, estrogen. When some forms of breast tumors are exposed to estrogen they can grow larger and spread further than when no or lower levels of estrogen are present. This is because the tumors have estrogen receptors. If estrogen is helping the tumors grow, then removing estrogen would be an ideal solution.

Estrogen can be removed in two different ways; by blocking it from binding to receptors on the tumors, or by reducing its production in the body – which is what happened when surgeons removed the ovaries. Tamoxifen works by blocking estrogen receptors on breast cancer cells.

Image from River Pharmacy

Tamoxifen has a very unusual origin story. Scientists first began developing the drug in the 1960s as a contraceptive to reduce fertility by blocking estrogen. When they tested it in rats, the rats were less fertile. But when tested in mice, the mice were more fertile. This paradoxical effect made scientists uncertain about how it would affect humans. Through clinical trials in the early 1970s, scientists determined that the drug also increased fertility in human women, and was thus marketed to induce ovulation in women and also to treat breast cancer in post-menopausal women because of how it worked to block estrogen receptors.

The reason this anti-estrogen drug can increase fertility rather than be used as a contraceptive is because it blocks estrogen from attaching to estrogen receptors. This means there is more estrogen in the body, thus increasing fertility. This is also why Tamoxifen is more useful in post-menopausal women than pre-menopausal women.

Tamoxifen isn’t the only anti-estrogen drug that is used to treat breast cancer. The American Cancer Society is a great source for more information about other current treatments such as aromatase inhibitors and ovarian suppression.

Patient Derived Xenograft, a future therapy

Now I turn to a future breast cancer therapy – patient derived xenografts. We have previously discussed patient derived xenografts in one of our research roundups. These xenografts work by taking tumor cells from patients and directly implanting them into mice. These patient tumors in the mice can then be studied to learn how they might grow/spread, and which therapies might be most effective.

One reason this tool is so important is because it can provide a more personalized approach towards caring for the patient. It is even more important for breast cancer because breast tumor cells grow and spread differently for each patient – the cancer is very diverse. By growing each patient’s unique cancer, we may be able to tailor treatments to specific patients and learn more about breast cancer in general.

Patient derived xenografts, however, are not a cure-all and there is still much we need to research. As covered in the research roundup, the tumor cells may grow differently in mice than they would in a human. Thus, just because a therapy might work for a mouse it does not necessarily mean it will work for a human. Also, for these xenografts to be effective, we need to reduce the amount of time it takes for scientists to test the tumors in the mice without compromising the translational power of the mice. For example, we could increase how fast the tumors spread in the mice, but that may compromise the tumors to a point where they are no longer similar to the tumors in the patient.

The end of a series…

We hope that you have enjoyed this series, “Of Mice and Mammaries.” Not only should this series educate our readers about breast cancer and animal research, it should also demonstrate the importance of animal research in treating disease.

In the early 1900s the mouse was viewed as an unsuitable model for humans because the virus, MMTV, that spread breast cancer in mice was never identified in humans. But through further research, scientists could generate genetically engineered (GE) mice and through rigorous validation, provided evidence of the suitability of these (GE) mice as models for humans. They then could test drug therapies, such as Tamoxifen, on these animal models and later develop future patient derived xenograft models.

When research is in early stages, it is often difficult to determine when and how it will help humans or other animals. Sometimes, research is based on an idea. But, over time the idea may grow as evidence accumulates with respect to its relevance and efficacy, and, in turn, may continue in a new direction. These new directions often lead to great breakthroughs, and these breakthroughs, in turn, may help humans.  The story of mice and mammaries is a great example of this process.

Justin Varholick

References

  1. Jordan VC. (2003). Tamoxifen: a most unlikely pioneering medicine. Nature Reviews, Drug Discovery. 2.
  2. Whittle JR, Lewis MT, Lindeman GJ, Visvader JE. (2015). Patient-derived xenograft models of breast cancer and their predictive power. Breast Cancer Research. 17(17).

Research Roundup: Alzheimer’s disease in the wild, second CAR-T therapy approved 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.

  • Traces of Alzheimer’s Disease Detected in Wild Animals for the First Time. Researchers, including Simon Lovestone of Oxford University, have found evidence of Alzheimer’s in dolphins.  Dr. Lovestone asked the question, “Are dolphins, as a result of their long lives, susceptible to age-related neurological diseases, such as Alzheimer’s?”  To find the answer, he and his colleagues studied the brains of wild dolphins who died naturally.  The researchers found two proteins that are referred to as “the smoking guns of Alzheimer’s disease in humans” in these wild dolphins’ brains. It is not known if dolphins experience the same cognitive symptoms. The latter question can only be studied with captive dolphins which is not being advocated for by these researchers. They are hopeful that comparative studies of dolphin and human brains with Alzheimer’s will show what factors are responsible for the disease in order to develop treatments in the future.  This study was published in Alzheimer’s and Dementia.

Image credit: University of Oxford

  • Ottawa researchers develop new animal model for a rare, debilitating childhood disease. Pyridoxine-dependent epilepsy (PDE) is a rare disorder that causes infants and young children to suffer from prolonged seizures and related neurological problems which do not respond to commonly used epilepsy medications. Currently, symptoms are managed with large doses of pyridoxine, also known as vitamin B6. A team including researchers from the University of Ottawa and the Children’s Hospital of Eastern Ontario have developed a model for PDE using zebrafish that share the same genetic mutation as affected children. Newly hatched and very young zebrafish show similar epileptic and neurological symptoms which also respond to treatment with vitamin B6. The hope with this new animal model for PDE is for the development of new treatments, and better outcomes for the affected children. This research was published in Genetics.
  • A little myelin goes a long way toward restoring nervous system function. Myelin, the lipid/protein sheath that surrounds and protects nerve fibers, is critical for electrical signaling in the brain and for quickly sending nerve impulses from the brain to the body. Though it is well known that diseases of the nervous system, like multiple sclerosis, degrade myelin, what remains to be discovered is how myelin naturally repairs itself and whether thin myelin sheaths can restore brain circuitry over the long term. Researchers at the University of Wisonsin-Madison, studying a unique but common genetic mutation in Weimaraner dogs and remyelination of the optic nerve in cats, reported this week that renewed but thin myelin sheaths are sufficient to restore the impaired nervous system. Moreover, they can do so years after disease onset. These important findings confirmed that the gold standard for evaluating remyelination is the long-term persistence of myelin sheaths, which support nerve fiber function and survival. Future research will now be able to leverage this knowledge to test new therapies designed to promote myelin repair. The study was reported in the Proceedings of the National Academy of Sciences USA.

The normal mature dog spinal cord (A) has many axons surrounded by thick myelin sheaths (blue). In contrast, in the recovered 13-year-old dog with the genetic abnormality (B), there are many axons with thin myelin sheaths, identical to that seen in remyelination. Source.

  • FDA Approves Second CAR T-Cell Therapy. CAR T is a pioneering type of gene therapy for cancer. CAR T-cells are equivalent to given patients a “living drug”. “The therapy requires drawing blood from patients and separating out the T cells. Next, using a disarmed virus, the T cells are genetically engineered to produce receptors on their surface called chimeric antigen receptors, or CARs.” While this form of therapy has been in use in various small scale human trials, it is the second approval in the world for a type of CAR T therapy. Much of its success is due to pre-clinical safety and efficacy testing in animals models, such as mice — which we have covered previously. The “living drug”, known as Yescarta is produced by Kite Pharma and owned by Gilead Sciences and is approved for use against some types of large B-cell lymphomas. It costs 373,000 USD for the life-saving treatment.
  • Secrets to how rabies causes aggressive behavior untangled. Rabies is a viral disease which leads to encephalitis (inflammation of the brain) in mammals. While much is known about rabies, including our ability to vaccinate against it, a lot is unknown about how the rabies virus “hijacks” the brain and leads to aggressive behaviour. These researchers, using mice, investigated whether the rabies glycoprotein, which accumulates in the brain after virus exposure leads to behavioral changes. Dr. Harris, the lead researcher of this study stated, “When we injected this small piece of the virus glycoprotein into the brain of mice, the mice started running around much more than mice that got a control injection. Such a behavior can be seen in rabies-infected animals as well.” This research was published in the journal Scientific Reports.

Join us at the 5th International Conference of the Basel Declaration Society in February 2018

The 5th International conference of the Basel Declaration Society, focused on “Openness and Transparency: Building Trust in Animal Research” will take place in San Francisco on the 14th – 15th February 2018. Four Speaking of Research committee members will be involved as speakers or workshop leaders – Allyson Bennett (also University of Wisconsin), Paula Clifford (also Americans for Medical Progress), Tom Holder, and Kirk Leech (also European Animal Research Association).

The conference is free to attend (on a first come first serve basis), and the deadline for registration is 1st December 2017. So register today! The full conference program provides an insight on what promises to be an interesting and useful day on animal research communication.

The conference aims to provide “a unique opportunity for all stakeholders from academia and industry to meet and discuss best-practice examples of improved open communication and other innovative efforts to increase trust [in animal research]”. It has been convened by Americans for Medical Progress, Foundation for Biomedical Research, National Association for Biomedical Research, and the Basel Declaration Society.

Speaking of Research committee involvement:

  • Kirk Leech, who is also the Director of the European Animal Research Association, will discuss “How greater openness with the public can ease pressures on the animal research supply chain”
  • Tom Holder, Director of Speaking of Research, will provide “The case for openness: why institutions benefit from a proactive approach to animal research communication”. He will also be leading a workshop on “Science Communication and Social Networks”
  • Paula Clifford (also AMP) and Allyson J. Bennett (also University of Wisconsin) will jointly lead a workshop on “Openness and transparency in animal research”. The aim of this workshop is to work on a written document that can be seen as a commitment to a process aiming to increase openness and transparency concerning animal research in the USA.

UCLA scientist and former SR committee member, Dario Ringach, will also be speaking on the “Moral disputes on science”.

Read the full program.

By bringing together speakers from Europe and North America, the conference hopes to share some of the best examples of openness from across the developed world. This comes during a time of falling public support for animal research in both the US and UK (though the UK saw a slight uptick in support in the most recent polls).

Credits: J. You/Science; (Data) Ipsos MORI, Gallup

Our animal research statement list continues to lengthen, suggesting a greater number of institutions committing to being more open about their animal research. Yet many institutions in many countries still do not acknowledge the animal research they so publicly. The list shows a diversity of available information – with many institutions providing all manner of information, case studies, images and videos, while many more provide only the briefest mention of their own scientific endeavors.

We hope many of you will be able to join us at the Basel Declaration Society conference in February, so register today!

Of Mice and Mammaries, Part 3: Modelling Human Breast Cancer

In light of Breast Cancer Awareness Month, Justin Varholick traces how mice have helped breast cancer research over the past century. In the third post of this 4-part series, we look at advances made from the 1970s to present time and how mice are being used as a model for humans.

Over the past two weeks, in Parts 1 and 2 of this series, we discussed how scientists discovered mammary tumors in mice, and how some mice have the mouse mammary tumor virus (MMTV) – which spreads cancer to offspring through the mother’s milk. After scientists found it difficult to grow MMTV in a petri dish, they realized that they had to continue studying mammary tumors in the mouse itself. This week we will focus on how scientists validated – and are continuing to validate – mammary tumors in mice as a model for understanding human breast cancer.

Validating mice as a model for humans is not an easy task. Scientists must be able to show that the cause, development, or progression of the tumors are similar between mice and humans. However, human breast cancer is often caused by many different factors and does not always develop or metastasize consistently. Thus, scientists can only model certain aspects of breast cancer. For example, they might be able to model a cause of cancer but not the development or progression.

1975 to Present — Stem cells and pre-cancer stages

Stem cells of mammary tumors have become a valuable tool throughout the years because they allow scientists to study cells that may one day become cancerous, and determine ways to prevent them from becoming cancerous.

Original image by Science Magazine

Stem cells of mammary tumors were first identified in 1975 by Dr. Barry Pierce. Since this discovery, scientists have isolated these stem cells and tested different factors to prevent the stem cells from becoming cancerous. Unfortunately, no major findings to definitely prevent stem cells from becoming cancerous have been found.

Although no major findings have been found, stem cell research is very promising. Mice with mammary tumors that are caused by pre-cancerous stem cells often have tumors that are similar in shape to those found in humans. Thus, although we do not yet understand which factors may directly cause stem cells to become cancerous, the development and progression of the tumors in mice and humans are similar – making them a good model for research.

1980s to Present — Genetically Engineered Mice

While research on stem cells was underway, some scientists began exploring the idea of genetically engineering mice to have mammary tumors. This research would help scientists understand which genes are associated with mammary tumors, and also provide scientists with mice that reliably have mammary tumors from different genetic causes.

Genetically Engineered Mice

Because much research was already done on MMTV, the first genetically engineered (GE) mice were those that were genetically engineered to have MMTV. Unfortunately, GE mice with MMTV genes could not be used to understand human breast cancer. One reason was because human breast cancer is not caused by a virus. The second reason is because the types of tumors that develop from MMTV differ in cellular shape and structure compared to human tumors. Because mammary tumors in GE mice with MMTV are caused by different factors, and develop and progress differently, this makes them a poor model for research.

Although these first GE mice cannot be used as models, their creation helped scientists make different GE mice with tumors almost indistinguishable from human tumors. To make these GE mice, scientists inserted genes into mice that were associated with breast cancer in humans. These genes were erbB2 and myc. Because these genes caused mammary tumors in both humans and mice, this made them a good model for future research.

Unfortunately, breast cancer in humans is not always caused by genes. Some breast cancer is caused by abnormal hormone levels, carcinogens, and other factors that we do not yet understand. Also, because breast cancer has different causes this also means it has different pathways of development.

These differing factors make studying breast cancer difficult. But by studying more and more about mammary tumors in mice we may be able to build better models that will one day lead to better treatment options.

Justin Varholick

To be continued…

Tune in next week to learn which treatments scientists have discovered for humans by using mice as models. I will also cover the potential future of breast cancer research – patient derived xenografts.

References:

  1. Cardiff R, Kenney N. (2011). A compendium of the mouse mammary tumor biologist: From the initial observations in the house mouse to the development of genetically engineered mice. Cold Spring Harb Perspect Biol. 36(6).
  2. Medina D. (2010). Of Mice and Women: A Short History of Mouse Mammary Cancer Research with an Emphasis on the Paradigms Inspired by the Transplantation Method. Cold Spring Harb Perspect Biol. 2(10).
  3. Cardiff R, Couto S, Bolon B. (2011). Three interrelated themes in current breast cancer research: gene addiction, phenotypic plasticity, and cancer stem cells. Breast Cancer Research. 13(5).

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.

Of Mice and Mammaries, Part 2: Breast cancer in a dish?

In light of Breast Cancer Awareness Month, Justin Varholick traces how mice have helped breast cancer research over the past century. In the second post of this 4-part series, we look at advances made from 1960 to 1975 when scientists were studying a virus in the milk.

Last week, in Part 1 of this series, we discussed how scientists from the early 1900s studied the growth and spread of mammary tumors in mice. We also walked through an experiment discovering how the breast milk from mother mice carried “something” that was more responsible for breast cancer than the genes the mother had passed down to her pups. This week we learn how scientists determined that this new “something” was a virus, and this virus could only be found in mice – it was never found in humans.

1940 to 1960 — What’s in the milk?

After Dr. John Bittner found out that there was “something” in the milk, many scientists wanted to figure out what it was. A first thought was to filter the milk and see if it still showed the same effects as Dr. Bittner’s experiments. Scientists took very special filters used to filter out bacteria, and ran mouse milk from “high tumor” mothers through these filters. Despite filtering, the results remained the same – filtered milk from “high tumor” mothers still led to tumors in pups fed the milk.

Then in the early 1950s scientists started using electron microscopes to compare “high-tumor” mouse breast milk with normal “low tumor” mouse breast milk. The electron microscopes gave scientists the power to magnify the milk 2,000,000x the normal size – magnification beyond what the bacteria filters could filter out. After comparing the types of milk, Dr. Leon Dmochowski found many small particles in the “high tumor” milk and very few of these particles in the “low tumor” milk. After other scientists repeated these experiments, they concluded that these particles were the “something” in the milk that may be responsible for tumors in the pups. Many scientists looked for these particles in human breast tissue and milk, but could never find it – only mice have this “something” in the milk. It was interesting, however, that the particles were in both “high tumor” mothers and “low tumor” mothers, albeit in different amounts, which indicated that both types of mothers were at risk to have the mammary tumors – “high tumor” mothers just had a higher risk.

While all this science with electron microscopy was going on, scientists studying mammary tumor cells in mice determined that the something in the milk acted very much like a virus and gave it the name mouse mammary tumor virus, or MMTV for short.

Cover of “Immunity against the mouse mammary tumor virus” by Paula Creemers. Electron microscope image of MMTV with a sketch of two mice with mammary tumors.

1960 to 1975 — Can we grow the milk virus in a dish?

Now that scientists had established that a virus in the milk was responsible for mammary tumors in mice, they wanted to see if they could grow the virus in a petri dish. Scientists had already grown viruses in a dish that were responsible for cancer in chickens, and other viruses that were responsible for skin cancer in humans, so they believed they would be able to grow MMTV in the dish. Unfortunately, growing the milk virus dish proved very difficult.

In the 1970s many scientists tried to grow the virus in a dish and were unsuccessful. One group of scientists at the Cancer Research Genetics Laboratory (CRGL) of the University of California, Berkeley showed that the virus could be grown in a dish, but it was too cumbersome for many scientists to use for research. Because MMTV could not be easily grown in a dish, scientists interested in mammary tumors in mice knew they had to find a new method if they wanted to continue using mice to understand more about breast cancer.

To be continued…

Tune in next week, to learn how scientists started using new methods with stem cells to make genetically engineered mice and how they validated that the mouse could be used as a model for humans!

Justin Varholick

References:

  1. Cardiff R, Kenney N. (2011). A compendium of the mouse mammary tumor biologist: From the initial observations in the house mouse to the development of genetically engineered mice. Cold Spring Harb Perspect Biol. 3(6).