Category Archives: Science News

2017 SFN Attendees: Does your research depend on animal models?

If it does, consider adding this session to your conference plan:

What: SFN Animals in Research Panel. How to Effectively Communicate Your Animal Research:  Elevator Speech, Social Media, and Best Practices.  When & Where:  Monday November 13. Noon-2pm. Room 103A

Why? (as in, SFN is busy enough, why add a “non-new-science-discoveries-session” to your already packed science agenda?)

Reason 1) Did you answer “Yes, my research depends on animal models?” If so, communicating about your work via media and other public avenues can involve some challenges if you plan on accurately conveying your work.  

Sharing the findings, value, and excitement about research is something that scientists do through peer-reviewed publications, but also popular and public media. Communicating well—in an accessible and engaging way—about new discoveries can be a challenge in of itself. Good science communicators within university and institutional press offices can provide enormously valuable help. For those whose work depends on animal models, there are often unique challenges to public communication about the research. That may range from concern and fear about attracting the attention of opponents of animal research to uncertainly about how to talk about animal research to suppression by institutions who do prefer to remain low profile about their animal research programs.

The SFN panel addresses these challenges and can add to your tool-kit to assist you in broader dissemination of your work. The panel will be led by experts with extensive experience in public communication about animal research.  Together, the interactive panel will provide a basic understanding of, and show attendees strategies to engage with, various audiences on the importance and benefits of animal research.

The panelists include:

Amanda M. Dettmer, a senior editor for Speaking of Research, an international advocacy group that provides accurate information about the importance of animal research in biomedical science. Amanda obtained her PhD in Behavioral Neuroscience from the University of Massachusetts Amherst, and for over 15 years has been studying nonhuman primate models of human development and disease. She is currently working in Washington, DC, as the American Psychological Association’s 2017-18 Executive Branch Science Policy Fellow.

Paula Clifford, MA Executive Director, Americans for Medical Progress. Paula Clifford is the Executive Director for Americans for Medical Progress where she is leading national advocacy efforts. She creates and implements several innovative programs designed to provide information to the public about biomedical research and the role of animals in advancing medicine and science. Previously, she was the Executive Director for the PA Society for Biomedical Research (PSBR) where she led efforts to provide educational programs about biomedical research for K-12 classrooms.

Chris Barncard, Research Communications, University of Wisconsin-Madison. Chris writes about science at the University of Wisconsin-Madison, describing new insights on the world around us in a way that the uninitiated can understand. Alongside coverage of psychology, engineering and energy research, he helps researchers talk to journalists and the public about their work with animals. His work can be found at the UW-Madison animal research website where a dynamic news section is updated regularly with stories about the university’s research. Chris has also worked as a newspaper reporter, winning awards for coverage of elections, gambling and suicide.

Another reason to make time in your SFN schedule:  Did you answer “Yes, my research depends on animal models?” If so, your work also depends on public knowledge about animal research.  

Why? Because animal research may only be conducted if the public, through its elected representatives, continues to support legislation and regulation that allows for nonhuman animals to be involved in humane, well-regulated, and ethical research.

While you may know that such studies are only permitted in the US under a host of conditions mandated by federal law, it is safe to assume that there is a wide swath of the public—including voters, students, journalists, and policy-makers—who do not know.  You may know that:

  • Animal research is highly-regulated, with standards to protect animal welfare and oversight by institutional and federal agencies
  • Federally-funded research must balance scientific objectives with consideration of animal welfare
  • Laws require that animal research may only be conducted when there is no appropriate alternative to reach the scientific objective
  • Basic research is the foundation of discoveries that provide for new understanding of behavior, brain, biology and health
  • In turn, basic research – much of it with nonhuman animals – is critical to developing new prevention, treatment, and intervention to benefit human and animal health, society, and the environment

None of that may matter much though if the larger public is left in the dark.  Over the past decades, SFN has grown in size and new discoveries in neuroscience have proliferated to substantially advance understanding of the brain and health. At the same time, public opinion polls show a continuing decline in public approval for animal research. The gap between scientists and the public is large. In a recent PEW poll, for example, nearly 90% of AAAS sciences favored the continued use of animals in research, while less than 50% of the general public felt the same.

Opinion differences between the general public and AAAS scientists (adapted from Pew, 2015).

Is this what the scientific community thinks:  Not our job, not our problem?

The gap between opinions of scientists and those of the public is likely caused by many factors. Among them is the probability of differences in knowledge about why animal research is needed, what it has accomplished, when it is necessary, and how it is conducted—including how studies are evaluated, how animals are cared for, and how it is overseen.  Scientists can play an important role in engaging in public dialogue and informing the public about each of these topics.

Scientists have many responsibilities and demands on their time. After all, they are charged with doing science, writing papers and sharing science; with teaching and training students and next generation scientists; with service work that includes reviewing papers and grant proposals; and with generating new ideas, new avenues of discovery and obtaining funding to make the work happen.

None of that leaves a lot of time for public engagement and education about the big picture – why animal research is needed. In some cases, scientists believe that the job of public engagement and communication is one best left to others. Indeed, there are full-time organizations whose mission is entirely public outreach, education, and advocacy.  There are also full-time science communicators, public information officers, and others within our universities and research institutions whose job it is to engage with the public and share news about science.

Scientists themselves play a key role in communicating the science accurately and fully to the public. The SFN panel aims to provide scientists with tools for doing so and with information to carry back and facilitate efforts at their own institutions.

Want to do more?  Tweet, blog, and share!

If you’re planning to be at the SFN panel, please consider live-tweeting the session with hashtags #animalresearch #sfn17.  We will storify the tweets to provide a view for those who cannot attend (and to share with university and institutional communications offices).

Better yet, if you’d like to write a guest post summarizing the panel and your own take-away messages, please contact us or leave a comment below. We would love to provide space for SFN guest bloggers who would like to share why their research matters and why it depends on animal models.

Speaking of Research

 

Researchers Rally to Help Puerto Rico’s Monkey Island

A guest post by Lisa Howard of UCDavis explains the efforts by the National Primate Research Centers to help rebuild Cayo Santiago, better known as ‘Monkey Island’ rebuild after Hurricane Maria.

Primate researchers are rallying to help Puerto Rico’s “Monkey Island,” Cayo Santiago, which took a direct hit from Hurricane Maria in September. About a thousand rhesus macaques roam free on the 38-acre island, which is run by the Caribbean Primate Research Center and the University of Puerto Rico.

Although all the animals apparently survived, the island’s infrastructure and equipment – piers, buildings, rainwater collection systems, even the cages where researchers could eat lunch without it being stolen by monkeys – was destroyed. On the main island of Puerto Rico, the town of Punto Santiago, where the research center’s headquarters is located and where many staff live, was devastated, losing water, electricity and communications.

Directors of the seven U.S. National Primate Research Centers decided they needed to help Cayo Santiago rebuild. Professor John Morrison, director of the California National Primate Research Center at UC Davis noted:

We view CPRC as one of our sister centers, and fortunately, we were able to mobilize our response and deliver material in a very timely fashion. We are in constant communication with CPRC and stand ready to help in any way we can going forward,”

Each of the U.S. centers is contributing $5,000 to a fund to help Cayo Santiago. Darcy Hannibal, a project scientist at the CNPRC and colleagues worked to fill a shipping container with desperately needed supplies for both the field station’s staff and the research facility, including water, canned food, diapers, baby formula, tarps, water purification tablets and filters, chain saws and other equipment.

The researchers also prepared an emergency National Science Foundation grant application for Cayo Santiago to replace equipment.

Cayo Santiago, the oldest free-ranging research colony in the world for primates, took a direct hit from Hurricane Maria. The island’s infrastructure was obliterated. (Photo courtesy of Lauren Brent, University of Exeter)

Hannibal did her doctoral work at Cayo Santiago in 2004-5, observing feeding behavior in the monkeys. She and her colleagues at UC Davis hope they can get the word out about the importance of this unique research facility and get help for its people and animals.

All of the macaques on the island are descended from 409 monkeys brought to the island in 1938. All the animals are identified and their pedigrees are known, making it an invaluable resource for scientists who study primates. Researchers from universities in the United States and Europe use the island for a wide variety of primate behavior studies.

“There’s no other population that has so much long-term history,” said Hannibal. “It’s a remarkable resource for studying primates.”

In addition to supplies, Hannibal and other supporters are trying to raise cash for the facility. Two GoFundMe pages have been created, one for the staff, Relief for Cayo Santiago Employees, and one for the animals, Cayo Santiago Monkeys: Maria Relief. There is also a Facebook page, Friends of Cayo Santiago, where people can get updates about the damage and recovery efforts. Hannibal can be reached directly at dlhannibal@ucdavis.edu.

Lisa Howard

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).

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).

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).

 

Of Mice and Mammaries, Part 1: There’s something in the milk

In light of Breast Cancer Awareness Month, Justin Varholick traces how mice have helped breast cancer research over the past century. In the first post this 4-part series, we look at advances made from 1854 to 1940, including the understanding of the role of breast milk in causing certain types of tumors. 

Image credit: Jackson Labs

Breast cancer is one of the most serious forms of cancer facing women. Each year, over 300,000 women in the U.S. will be diagnosed with breast cancer, and it is estimated that 40,610 women will die from it in 2017 alone. Thankfully, death rates from breast cancer have dropped almost 40% from 1989 to 2015, and there are over 3.1 million breast cancer survivors living in the U.S. today.

Breast cancer grows and spreads through many stages, and can start in different parts of the breast. Some types of breast cancer cause lumps, others form no lumps. Some forms of it spread very quickly throughout the body, while others spread more slowly. Because breast cancer spreads and forms at different rates and in different areas of the breast, treating it is no easy task. It is also unlikely that we will one day have a “cure” for breast cancer — one size cannot fit all.

Despite the complicated nature of breast cancer, scientists feel a responsibility to understand it as much as possible in efforts to find new treatment methods and forms of a cure. Over the years they have made great strides in their research by studying mice. These mice serve as an essential step between early research on mammary cells and clinical trials in humans.

Over the course of this month, I will highlight some of the key findings scientists have discovered about breast cancer through their studies in mice.

1854 to 1903 — The first mouse mammary tumors

The first discovery of a mammary tumor in a mouse was in 1854. In these early days, scientists were able to find tumors spontaneously growing in female mice kept as pets and in the wild. Although they were able to detect and describe these tumors, it was difficult to understand where they came from, and how they grew and possibly spread or metastasized.

Thankfully in 1903, Dr. Carl Jensen developed a line of “high tumor” mice that readily grew mammary tumors, which could be easily transplanted to other mice. By transplanting the tumors in other mice, they could measure how and where the tumors spread, in otherwise healthy mice.

During this time in history, 1.2* women per 1,000 died from breast cancer in the U.S. Today it is around 0.13 women per 1,000. (*at this time we only had reports on the number of white women in the U.S.).

1933 to 1940 — There’s something in the milk

After bringing mice into the laboratory and thoroughly studying their biology, a great discovery was made — there was something in the milk. This discovery was made by Scientists at Jackson Laboratories, in Bar Harbor, Maine. They bred “high tumor” mice with “low tumor”* mice and found that offspring were more likely to get mammary tumors if they had a “high tumor” mother. Although some scientists were able to replicate this finding in other labs, very few were convinced there was something in the milk — they believed it was passed down through the genes. (* an extremely low number of “low tumor” mice were found with mammary tumors; because of this scientists could not call them “no tumor” mice.)

To answer whether there was either something in the genes or the milk, Dr. John J. Bittner did a more complex study 3 years later. In this key study, Bittner cross-fostered mouse pups from “high tumor” and “low tumor” mice to opposite mothers (see diagram). This method allowed him to determine whether the parent’s genes or the foster mother’s milk lead to mammary tumors. If it was the genes then “high tumor” offspring would have tumors whether they had “high tumor” or “low tumor” foster parents. If it was the milk then any offspring nursed by “high tumor” mothers would get tumors.

Through this experiment, Bittner found out that milk was a key factor. “Low tumor” pups cross-fostered to “high tumor” mothers had many mammary tumors, while “high tumor” pups cross-fostered to “low tumor” mothers had very few tumors. “High tumor” pups nursed by their own mothers, however, had the highest rates of tumor growth. It didn’t always matter who the parents were, it also mattered who nursed the pups. This verified that indeed there was something in the milk. This something was labeled as the Mouse Mammary Tumor Virus (MMTV).

Dr. Bittner was often heard stating that he only studied the milk because nobody else wanted it — they all wanted to study the genes.

To be continued…

Tune in next week to read what we learned about the milk virus, MMTV, and what we did with this new power!

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).
  2. Holen I, Speirs V, Morrissey B, Blyth K. (2017). In vivo models in breast cancer research: progress, challenges and future directions. Dis Model Mech. 10(4).
  3. Tarone RE, Chu KC. (1992). Implications of birth cohort patterns in interpreting trends in breast cancer rates. J Natl Cancer Inst. 84(18).