Charity Watchlist – Get Involved | American Life League

The list of charitable research organizations and their corresponding positions on the life issues posted to our website is neither all pro-life nor all anti-life; it is mixed. Unfortunately, most of the organizations on our list are marked with the red minus sign. It is simply just a sad fact that most national medical research/advocacy groups support some form of unethical research. There is no listing, to our knowledge, of only pro-life research organizations.

A green positive/plus sign indicates that ALL considers the organization worthy of support from pro-lifers. ALL considers an organization to be pro-life if it is opposed to abortion, human embryonic stem cell and/or aborted fetal body parts research, all forms of cloning and other attacks against the human person at any stage of development as well as Planned Parenthood Federation and other pro-abortion organizations.

A red negative/minus signs indicates that ALL does not consider the organization worthy of support from pro-lifers. If the organization supports, in any way (theory, advocacy, lobbying, granting and/or research) any offenses to life, it is not considered pro-life. Further, if any organization refuses to answer our inquiries, refuses to be clear about its position and/or attempts to couch its answer in terms of referring to another agency (i.e., federal government branches), it is not considered pro-life.

A plain yellow circle indicates that ALL urges caution when considering support for the organization due to a change in a prior rating. That is, an organization may have previously received a green positive or a red negative because of certain policy positions which are now questionable or cannot be verified.

The rating is based on the organizations response to written correspondence (regular postal or e-mail), a review of the organizations website, verifiable news reports, verifiable correspondence forwarded to us by others and/or a combination of any of these.

Research into other organizations not listed is an on-going process, but may be limited by staff and resources at ALL. If you have information (and documentation) about organizations that you would like to see listed, we would be most happy to receive it. Currently, we are not in a position to print the list (it amounts to more than 100 pages, not including documentation in hyperlinks) however, feel free to pass the link to the website to everyone you know!

Alex's Lemonade Stand Foundation 333 E. Lancaster Ave Suite 414 Wynnewood, PA 19096 Phone: 866-333-1213 Fax: 610-649-3038 http://www.alexslemonade.org Liz Scott, Alex's mother and co-executive director of Alex's Lemonade Stand Foundation, stated in an e-mail to ALL in May, 2012, that: "Alex's Lemonade Stand Foundation has not funded anything even remotely related to embryonic stem cell research."

However, when it was pointed out to Mrs. Scott that, according to the Foundation's website, there were grant funds being directed toward researchers and research facilities that support, promote and conduct such research, she responded:

"Although we have not issued a public policy position, I can tell you that ALSF has always followed all federal guidelines for research that involves human-derived cells and tissues. We are very sensitive to the variety of opinions on issues related to stem cells, and are committed to funding research programs that meet all of the stringent ethical standards at the institutional, foundation and government levels, that are designed to find cures for childhood cancer. I can tell you that when we award funds to our grant recipients 100% of the funds are used for their project onlythe institution is not allowed to take any indirect costs or general operating costs from the award funds or to use funds for other projects."

ALL cautions that federal guidelines allow for both human embryonic stem cell research and the use of aborted fetal materials in research.

When contacted by email in July 2014 with an update request, someone by the name of Lisa responded:

We do not have a policy. We have never received an application that includes embryonic stem cells so this isnt an issue for us.

When asked what the organization would do if it did receive a grant application that involved the use of human embryonic stem cells or aborted fetal material, there was no further reply.

Alliance for Aging Research 1700 K Street, NW Suite 740 Washington, DC 20006 Phone: 202-293-2856 Fax: 202-955-8394 http://www.agingresearch.org The Alliance for Aging Research is a 501(c)(3) group that advocates for medical research and scientific discoveries to improve the health and independence of Americans as they age. As such, the Alliance supports public policies that advance research involving both adult and embryonic stem cells and regenerative medicine in general.

While the Alliance for Aging Research opposes efforts to copy human life through cloning technologies, it is a leader among patient groups and science advocates supporting public funding for broad activities in stem cell research as well as therapeutic cloning of compatible stem cell lines for research and potential therapies. On its own and through membership in the Coalition for the Advancement of Medical Research, the Alliance will support the enactment of legislation to encourage increased federal funding for advances in stem cell research. https://web.archive.org/web/20130907070614/http://www.agingresearch.org/content/topic/detail/?id=1018&template=position

UPDATE: July 2, 2014

In an email to ALL from Noel Lloyd, Communications Manager at AAR:

The Alliance supports public policies that advance medical research with the potential to prevent, postpone or otherwise lessen diseases and disabilities that increase with aging. This includes policy support though not direct funding of a broad scope of regenerative medicine, including research on induced pluripotent and human embryonic stem cells.

Alliance for Regenerative Medicine 525 2nd Street, N.E. Washington, DC 20002 Phone: 202-568-6240 http://www.alliancerm.org "The Alliance for Regenerative Medicine (ARM)s mission is to advance regenerative medicine by representing, supporting and engaging all stakeholders in the field, including companies, academic research institutions, patient advocacy groups, foundations, health insurers, financial institutions and other organizations."

According to the website, regenerative medicine includes cell-based therapies, gene therapy, biologics, tissue engineering, bio-banking, and stem cells for drug discovery, toxicity testing and disease modeling. It is this last branch of regenerative medicine which causes the most concern: "Companies are increasingly learning to leverage the use of stem cells and/or living tissue constructs to create in vitro models to study human mechanisms of disease and the effects of drugs on a variety of cell and tissue types such as human heart, liver and brain cells. These models, built predominantly using embryonic and induced pluripotent stem cells, allow for faster and safer drug development." (http://alliancerm.org/industry-snapshot)

Many of ARM's membersare companies, foundations, and associations with public positions of support for human embryonic stem cell research.

ALS Association (Amyotrophic Lateral Sclerosis Association) 1275 K Street, NW Suite 250 Washington, DC 20005 Phone: 202-407-8580 http://www.alsa.org In an email to ALL from Carrie Munk at the ALS Association July 2, 2014:

The ALS Association primarily funds adult stem cell research. Currently, The Association is funding one study using embryonic stem cells (ESC), and the stem cell line was established many years ago under ethical guidelines set by the National Institute of Neurological Disorders and Stroke (NINDS); this research is funded by one specific donor, who is committed to this area of research. In fact, donors may stipulate that their funds not be invested in this study or any stem cell project. Under very strict guidelines, The Association may fund embryonic stem cell research in the future.

The ALS Association also financially supports NEALS (the Northeast ALS Consortium) which performs human embryonic stem cell research:

The ALS Association Awards $500,000 to the NEALS Consortium for Its TREAT ALS Clinical Trials Network For the sixth consecutive year, The ALS Association is pleased to announce its support of the Northeast ALS Consortium (NEALS), the largest consortium of ALS clinical researchers in the world. This years award totals $500,000 and will fund new initiatives and ongoing programs that will increase the quality and efficiency of clinical trials for ALS. (www.alsa.org/news/archive/neals-consortium-award.html)

The Northeast ALS Consortium (NEALS) is an international, independent, non-profit group of researchers who collaboratively conduct clinical research in Amyotrophic Lateral Sclerosis (ALS) and other motor neuron diseases.

Study utilizing the spinal cord neural stem cells from electively aborted fetus.

Alzheimer's Association 225 N. Michigan Avenue Floor 17 Chicago, IL 60601-7633 Phone: 312-335-8700 Fax: 866-699-1246 http://www.alz.org The Alzheimers Association policy supports and encourages any legitimate scientific avenue that offers the potential to advance this goal, including human embryonic stem cell research; and, we oppose any restriction or limitation on research, provided that appropriate scientific review, and ethical and oversight guidelines and compliance are in place." http://www.alz.org/national/documents/statements_stemcell.pdf

American Cancer Society 250 Williams St., NW Atlanta, GA 30303 Phone: 800-227-2345 http://www.cancer.org The American Cancer Society is not considered a pro-life organization for the following reasons:

Support for human embryonic stem cell research

The American Cancer Society (ACS) has, for many years, insisted that the federal government remains the institution best suited to both fund and oversee research using human embryonic stem cells while claiming to fund only explorations into uses of human adult stem cells and stem cells from umbilical cord blood.

However, in August 2001, when then-President Bush signed an executive order restricting federal funding of human embryonic stem cell research to stem cell lines that were already in existence at the time, the ACS issued a statement commending the administration for allowing stem cell research to proceed, and expressed hope for its future.

The Society believes that such research holds extraordinary potential in the fight against a variety of life-threatening diseases currently afflicting an estimated 140 million Americans, the statement said. It continued, The American Cancer Society commends the Administration for allowing this vital scientific research to proceedeven in a limited way.

The American Cancer Society remains hopeful that both the government and commercial sectors will continue to work collaboratively and with an open mind to explore additional solutions that will allow for the continuation of human embryonic stem cell research as necessary and appropriate, the ACS statement concluded.

These statements can no longer be found on the ACS website, but can be viewed here: http://replay.waybackmachine.org/20030626004233/http://www.cancer.org/docroot/NWS/content/NWS_1_1x_President_Supports_Limited_Stem_Cell_Research.asp

Keep in mind that during the eight years that followed Bushs order, Congress passed legislation to expand human embryonic stem cell research and each time it was vetoed. When President Barack Obama took office in 2009, one of his first acts as president was to issue an executive order expanding the research policy. The National Institutes of Health (NIH) began funding grants in the field of human embryonic stem cell research.

No ACS grants which provide for the direct funding of human embryonic stem cell research have been identified; however, grant funding to facilities and labs where such research abounds is indeed prominent.

The American Cancer Society has, in the past, also awarded financial grants to Planned Parenthood, the nations leading provider of abortion. http://www.lifesitenews.com/news/american-cancer-society-gives-planned-parenthood-grant-money-for-just-sayin

Despite the outcry over the connection to Planned Parenthood, the ACS maintains the association. Visitors to the ACS website can type Planned Parenthood into the search field and find a number of results:

Referral to Planned Parenthood as source of information and support for testicular cancer: http://www.cancer.org/cancer/testicularcancer/moreinformation/doihavetesticularcancer/do-i-have-testicular-cancer-add-res and http://www.cancer.org/acs/groups/cid/documents/webcontent/003172-pdf.pdf

Referral to Planned Parenthood as source of information and support for cervical cancer: http://www.cancer.org/cancer/cervicalcancer/overviewguide/cervical-cancer-overview-additional

The ACS refers to Planned Parenthood as a Voluntary Health Organization which should be invited into schools: http://www.cancer.org/acs/groups/content/@nho/documents/document/keycommunityrepresentativespdf.pdf

Planned Parenthood affiliate locations are used as sites for ACS awareness activities: http://www.cancer.org/myacs/eastern/areahighlights/cancernynj-news-blue-albany

The ACS notes that use of IUDs correlate with decreased risk of cervical cancer and that multiple pregnancies correlate to increased risk. The ACS recommends the HPV vaccine (Gardasil or Ceravax). The ACS also lists Planned Parenthood Federation of America as a source of information and support concerning HPV. http://www.cancer.org/acs/groups/cid/documents/webcontent/003042-pdf.pdf

J. Diane Redd, ACS Director for Major and Planned Gifts for New Jersey is a former fundraiser for Planned Parenthood: https://www.cancer.org/involved/donate/otherwaystogive/plannedgiving/diane_redd

Mady J. Schuman, a member of ACS' executive leadership used to work for Planned Parenthood: https://www.cancer.org/involved/donate/otherwaystogive/plannedgiving/mady_schuman

Kris Kim, ACS' CEO for the Eastern Division was the associate vice president for communications at Planned Parenthood New York City: http://www.cancer.org/acs/groups/content/@eastern/documents/document/acspc-028409.pdf

Similarly, the American Cancer Society has links to another pro-hESCR/pro-abortion organizationLance Armstrongs LIVESTRONG. The ACS is listed as an ambassador to the LIVESTRONG Global Cancer Campaign in honor of Lance Armstrongs return to professional cycling (http://www.livestrong.org/Who-We-Are/Our-Strength/LIVESTRONG-Societies/Ambassadors). Ambassadors committed to donating $250,000 or more in 2009.

Lance Armstrong supports human embryonic stem cell research http://livestrongblog.org/2009/03/09/president-obama-lifts-stem-cell-funding-ban/ and the LIVESTRONG Foundation lists abortion providers on its website. http://www.livestrong.com/search/?mode=standard&search=planned+parenthood

Aside from the American Cancer Societys support for human embryonic stem cell research and questionable grant funding, it refuses to acknowledge the abortion/breast cancer link and declines to even support the idea that doctors should mention it to their patients. Source: http://www.abortionbreastcancer.com/newsletter102202.htm

Lastly, in its document on fertility in women with cancer, the ACS suggests egg freezing, embryo freezing, in vitro fertilization, egg donation, and surrogacy. http://www.cancer.org/acs/groups/cid/documents/webcontent/acspc-041244-pdf.pdf

And, in its document on fertility in men with cancer, the ACS suggests sperm banking, sperm donation and in vitro fertilization. http://www.cancer.org/acs/groups/cid/documents/webcontent/acspc-041228-pdf.pdf

American Council on Science and Health 1995 Broadway Suite 202 New York, NY 10023-5860 Phone: 866-905-2694 Fax: 212-362-4919 http://www.acsh.org The American Council on Science and Health (ACSH) is a consumer education consortium concerned with issues related to food, nutrition, chemicals, pharmaceuticals, lifestyle, the environment, and health. ACSH was founded in 1978 by a group of scientists who had become concerned that many important public policies related to health and the environment did not have a sound scientific basis. These scientists created the organization to add reason and balance to debates about public health issues and to bring common sense views to the public. http://www.acsh.org/about/

Im pleased with the courts [U.S. appeals court rules in favor of stem cell research, August 2012] decision, says ACSHs Dr. Gilbert Ross, since stem cells have such vast potential to solve currently insoluble medical problems, including illnesses such as ALS and perhaps, eventually, Alzheimers disease. Certainly, to continue scientific advances in this field, research on stem cells must not be discouraged. http://acsh.org/2012/08/u-s-appeals-court-rules-in-favor-of-stem-cell-research/

ACSH has been a fervent advocate for supporting research progress in ESCs (embryonic stem cells) for years, despite the controversy involving the objections of some to using human embryonic tissues in research. http://acsh.org/2013/07/small-step-in-stem-cell-research-a-giant-leap-for-mankind/

American Diabetes Association National Office 1701 N. Beauregard St. Alexandria, VA 22311 Phone: 800-342-2383 http://www.diabetes.org We strongly support the protection and expansion of all forms of stem cell research, which offer great hope for a cure and better treatments for diabetes. We support legislation and proposals that enhance funding for stem cell research at the federal and state levels. http://www.diabetes.org/advocacy/advocacy-priorities/funding/stem-cell-research.html#sthash.PUBLIjKV.FhjarP2n.dpuf

The American Diabetes Association applauds President Obama for issuing an Executive Order that will advance stem cell research by lifting existing restrictions on the use of embryonic stem cells, while maintaining strict ethical guidelines.

The American Diabetes Association has long been a strong advocate for ending the current restrictions on stem cell research. http://www.diabetes.org/newsroom/press-releases/2009/statement-from-the-american-2009.html

American Heart Association National Service Center 7272 Greenville Ave Dallas, TX 75231 Phone: 800-242-8721 http://www.heart.org The American Heart Association website states the following regarding stem cell research:

Stem Cell Research The American Heart Association funds meritorious research involving human adult stem cells because it helps us fight heart disease and stroke. We dont fund research involving stem cells derived from human embryos or fetal tissue.

However, it continues:

Inducing adult stem cells into a pluripotent state may lead to patient-specific cell therapies that could reduce many of the underlying complications in therapies with embryonic stem cells.

Its important for research to continue in both cell types. To know how induced adult stem cells need to perform, we must know more about the innate function of embryonic stem cells. http://www.heart.org/HEARTORG/Conditions/Research-Topics_UCM_438796_Article.jsp

American Lung Association 55 Wacker Dr., Suite 1150 Chicago, IL 60601 Phone: 312-801-7630 http://www.lung.org The American Lung Association recognizes that research with human stem cells offer significant potential to further our understanding of fundamental lung biology and to develop cell-based therapies to treat lung disease. The American Lung Association supports the responsible pursuit of research involving the use of human stem cells. http://www.lung.org/get-involved/advocate/advocacy-documents/research.pdf

American Medical Association AMA Plaza 330 N. Wabash Ave., Suite 39300 Chicago, IL 60611-5885 Phone: 80-262-3211 http://www.ama-assn.org "The principles of medical ethics of the AMA do not prohibit a physician from performing an abortion in accordance with good medical practice and under circumstances that do not violate the law." http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion201.page?

The AMA supports the legal availability of mifepristone (RU-486) for appropriate research and, if indicated, clinical practice. (Res. 100, A-90; Amended: Res. 507, A-99) http://www.ama-assn.org/ad-com/polfind/Hlth-Ethics.pdf

The AMA reaffirms its position in support of the use of fetal tissue obtained from induced abortion for scientific research. (Res. 540, A-92; Reaffirmed: CSA Rep. 8, A-03) http://www.ama-assn.org/ad-com/polfind/Hlth-Ethics.pdf

Our AMA (1) supports continued research employing fetal tissue obtained from induced abortion, including investigation of therapeutic transplantation; and (2) demands that adequate safeguards be taken to isolate decisions regarding abortion from subsequent use of fetal tissue, including the anonymity of the donor, free and non-coerced donation of tissue, and the absence of financial inducement. (Res. 170, I-89; Reaffirmed by Res. 91, A-90; Modified: Sunset Report, I-00) http://www.ama-assn.org/ad-com/polfind/Hlth-Ethics.pdf

American Parkinson's Disease Association National Office 135 Parkinson Avenue Staten Island, NY 10305 Phone: 800-223-2732 Fax: 718-981-4399 http://www.apdaparkinson.org "We were very pleased on September 28, 2010 that the DC Circuit Court of Appeals issued a stay of the preliminary injunction pending its review of the appeal of the judicial challenge to federal funding for human embryonic stem cell (hESC) research. Without getting mired down in all the various terms and courts, what this means is that federal funding for hESC research will continue at least for the time period that it takes for the Court of Appeals to review Judge Lamberth's August 23rd decision to enjoin funding. You should also know that yesterday the Coalition for the Advancement of Medical Research (CAMR), of which PAN is a founding member, filed an amicus brief in the District Court. This brief supports and compliments the Department of Justice (DoJ) brief that was filed on behalf of the National Institutes of Health (NIH) on Monday."

[Department of Veteran Affairs and APDA Winter 2011 Parkinson Press Newsletter] http://bit.ly/1nsENqi

American Red Cross 2025 E. Street NW Washington, DC 20006 Phone: 202-303-4498 http://www.redcross.org A report issued from the International Federation of the Red Cross and Red Crescent in December of 2011 caused concerns that the organization may start advocating for abortion rights.

In a section of the report on human rights, IFRC quotes a widely criticized document issued by Anand Grover, the UN Special Rapporteur on the Right to Health, which said,

"States must take measures to ensure that legal and safe abortion services are available, accessible, and of good quality." The IFRC report goes on to editorialize, "But the real challenge is to find out how many states will indeed change their policies accordingly.

This may lead some to believe IFRC could eventually declare abortion a human right as Amnesty International did in 2007. Amid much controversy, Amnesty International simply announced that endorsing abortion as a right was a "natural" outgrowth of its 2-year campaign countering violence against women. http://www.c-fam.org/fridayfax/volume-14/analysis-is-the-red-cross-about-to-declare-abortion-a-human-right.html.

There have been no further developments in this area.

The American Red Cross has no formal public policy statements that we could find on life issues. It should be noted, however, that the American Red Cross has been under intense scrutiny and has been sued repeatedly by federal regulators to force improvements in blood safety. http://www.forbes.com/sites/gerganakoleva/2012/01/17/american-red-cross-fined-9-6-million-for-unsafe-blood-collection/

The American Red Cross also has a Diversity Program which officially recognizes and encourages participation in Gay and Lesbian Pride Month. American Red Cross Fires Employee for Refusal to Celebrate 'Gay and Lesbian Pride Month,' LifeSiteNews, August 5, 2005

American Spinal Injury Association 2020 Peachtree Road, NW Atlanta, GA 30309 Phone: 404-355-9772 Fax: 404-355-1826 ASIA_Office@shepherd.org http://asia-spinalinjury.org/ ASIA is a multidisciplinary organization whose membership is composed of physicians and allied health professionals specifically involved in spinal cord injury management. Current membership numbers 452 of which 85% are physicians. The remaining 15% are nurses, therapists, psychologists and other allied health professionals.

ASIA positions on the life topics are not clear; ALL is awaiting a response to our inquiry.

American Thoracic Society 25 Broadway New York, NY 10004 Phone: 212-315-6498 http://www.thoracic.org The American Thoracic Society (ATS) is an organization dedicated to serving patients with lung disease through research, advocacy, training, and patient care. As such, it supports making federal funding available for research using human embryonic stem cells with appropriate guidelines and federal and institutional oversight.

. . . [adult stem cell research] approaches should neither distract from nor preempt research for which the goal is to assess the use of pluripotent embryonic stem cells for the treatment of lung diseases. http://www.thoracic.org/statements/resources/research/stemcell.pdf

Amnesty International US 5 Penn Plaza New York, NY 10001 Phone: 212-807-8400 http://www.amnestyusa.org Amnesty International defends access to abortion for women at risk In April 2007, Amnesty International changed its neutral stance on abortion to supporting access to abortion in cases of rape and incest, and when the life or the health of the mother might be threatened. Amnesty's official policy is that they "do not promote abortion as a universal right" but "support the decriminalisation of abortion". http://www.amnesty.org/en/library/asset/POL30/012/2007/en/c917eede-d386-11dd-a329-2f46302a8cc6/pol300122007en.pdf

Amnesty International Continues Pushing Abortion Worldwide (2013) Amnesty International, a human rights organization that used to be abortion neutral, is now using the problem of maternal mortality to advocate for abortion. In a new report, ostensibly on medical care for maternal health, Amnesty calls on governments to repeal abortion laws and conscience protection for medical workers who may object. They also call for public health systems to train and equip health care providers to perform abortions.

Amnestys Maternal Health is a Human Right campaign focuses attention on four countries: Sierra Leone, Burkina Faso, Peru, and the United States. Amnesty argues that maternal mortality will decrease if it is treated as a human rights issue, if costs to health care are covered by governments, and if a right for women to control their reproductive and sex lives is established. http://www.lifenews.com/2012/08/09/amnesty-international-continues-pushing-abortion-worldwide/ http://www.amnestyusa.org/our-work/campaigns/demand-dignity/maternal-health-is-a-human-right

Amnesty International Launches New Campaign to Push Abortion Worldwide (2014) Amnesty International has been under fire for years for its pro-abortion positions and now the venerable human rights group is launching a new global effort to push abortion on a worldwide scale. The My Body My Rights campaign encourages young people around the world to know and demand their right to make decisions about their health, body, sexuality and reproduction without state control, fear, coercion or discrimination. It also seeks to remind world leaders of their obligations to take positive action, including through access to health services, the group says. http://www.lifenews.com/2014/03/10/amnesty-international-launches-new-campaign-to-push-abortion-worldwide/

"Amnesty International believes that everyone should be free to make decisions about if, when and with whom they have sex, whether or when they marry or have children and how to best protect themselves from sexual ill-health and HIV." http://www.amnesty.org/en/news/sexual-and-reproductive-rights-under-threat-worldwide-2014-03-06

Avon Foundation for Women 777 Third Avenue New York, NY 10017 Phone: 866-505-2866 http://www.avonfoundation.org The Avon Foundation for Women is a 501(c)(3) public charity founded in 1955 with the mission to promote or aid charitable, scientific, educational, and humanitarian activities, with a special emphasis on those activities that improve the lives of women and their families. In its work to realize those aspirations, the Foundations current mission focus is to lead efforts to eradicate breast cancer and end domestic and gender violence.

The Avon Breast Cancer Crusade was established in 1992. Since then, more than $815 million has been raised for breast cancer awareness and education, screening and diagnosis, access to care, support services and scientific research. Beneficiaries range from leading cancer research centers to local, nonprofit breast health programs, creating a powerful international network of research, medical, social service, and community-based breast cancer organizations.

The Avon Foundation is one of many breast cancer research fundraising groups that has yet to acknowledge the link between abortion and breast cancer.

While the Avon Foundation does not direct grant funding to Planned Parenthood, the more detailed answer on its website seems to indicate that it mightif it received a grant request that met its criteria.

Q: Does the Avon Foundation for Women support Planned Parenthood?

Our records indicate that in the last five years the Avon Foundation has received only one Planned Parenthood affiliate grant application from among more than an estimated 3,000 grant applications received during that time period, and it was not among our funded applicants. Our grant programs are highly competitive and unfortunately we receive many more quality applicants than available funds can support. Our Safety Net Program, Avon Breast Health Outreach Program and eight Avon Breast Health Centers of Excellence provide more than $15 million annually to address the needs for education, screening and treatment programs for underserved and uninsured women. http://www.avonfoundation.org/press-room/avon-foundation-for-women-response-to-recent-inquiries-about-breast-cancer-funding-support.html

The Speak Out Against Domestic Violence program was launched in the U.S. in 2004 and global expansion began shortly thereafter, with programs now in Central and South America and Europe. The Speak Out mission focuses on raising funds and awareness for domestic violence awareness, education and prevention programs while developing new community outreach and support for victims, and there is a special focus on supporting programs that assist children affected by domestic violence. Already more than $38 million has been awarded to over 250 organizations in the U.S.

In 2008, Avon Products, Inc. and the Avon Foundation introduced the company's first-ever global fundraising product, the Women's Empowerment Bracelet, designed to save and improve women's lives worldwide. The bracelet was unveiled by Avon Foundation Honorary Chair Reese Witherspoon at the second annual Global Summit for a Better Tomorrow, presented by the United Nations Development Fund for Women (UNIFEM) in partnership with Avon, at the United Nations in celebration of International Women's Day. Since then an entire catalog of fundraising products has been created.

UNIFEM is the United Nations Development Fund for Women. Established in 1976, it is self-described as fostering womens empowerment and gender equality and helping to make the voices of women heard at the United Nations. Two international agreements form the framework for UNIFEMs mission and goals: The Beijing Platform for Action and the Convention on the Elimination for All Forms of Discrimination Against Women (CEDAW).

In 1995, the Beijing Platform for Action (Beijing Platform) expressly called upon governments to reexamine restrictive abortion laws that punish women. By linking womens health to abortion law reform, the Beijing Platform affirmed what [pro-abortion] advocates [believe] worldwide: removing legal barriers to abortion saves womens lives, promotes their health, and empowers women to make decisions crucial to their well-being.

The Beijing mandate also reflects a global trend toward abortion law liberalizationa trend that first gained momentum in the late 1960s and continues to this day. http://reproductiverights.org/sites/default/files/documents/pub_bp_abortionlaws10.pdf

CEDAW, created in 1979, is actually a global Equal Rights Amendment. CEDAW mandates gender re-education, access to abortion services, homosexual and lesbian rights, and the legalization of voluntary prostitution as a valid form of professional employment. http://www.heritage.org/research/reports/2001/02/how-un-conventions-on-womens http://frcblog.com/2010/03/abortion-the-united-nations-and-cedaw/

See also http://www.all.org/newsroom_judieblog.php?id=2043.

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Charity Watchlist - Get Involved | American Life League

Stem cell controversy – Wikipedia

The stem cell controversy is the consideration of the ethics of research involving the development, use, and destruction of human embryos. Most commonly, this controversy focuses on embryonic stem cells. Not all stem cell research involves the human embryos. For example, adult stem cells, amniotic stem cells, and induced pluripotent stem cells do not involve creating, using, or destroying human embryos, thus are minimally, if at all, controversial. Many less controversial sources of acquiring stem cells include using cells from the umbilical cord, breast milk, and bone marrow, which are not pluripotent.

For many decades, stem cells have played an important role in medical research, beginning in 1868 when Ernst Haeckel first used the phrase to describe the fertilized egg which eventually gestates into an organism. The term was later used in 1886 by William Sedgwick to describe the parts of a plant that grow and regenerate. Further work by Alexander Maximow and Leroy Stevens introduced the concept that stem cells are pluripotent, i.e. able to become many types of different cell. This significant discovery led to the first human bone marrow transplant by E. Donnal Thomas in 1968, which although successful in saving lives, has generated much controversy since. This has included the many complications inherent in stem cell transplantation (almost 200 allogeneic marrow transplants were performed in humans, with no long-term successes before the first successful treatment was made), through to more modern problems, such as how many cells are sufficient for engraftment of various types of hematopoietic stem cell transplants, whether older patients should undergo transplant therapy, and the role of irradiation-based therapies in preparation for transplantation.

The discovery of adult stem cells led scientists to develop an interest in the role of embroynic stem cells, and in separate studies in 1981 Gail Martin and Martin Evans derived pluripotent stem cells from the embryos of mice for the first time. This paved the way for Mario Capecchi, Martin Evans, and Oliver Smithies to create the first knockout mouse, ushering in a whole new era of research on human disease.

In 1998, James Thomson and Jeffrey Jones derived the first human embryonic stem cells, with even greater potential for drug discovery and therapeutic transplantation. However, the use of the technique on human embryos led to more widespread controversy as criticism of the technique now began from the wider non-scientific public who debated the moral ethics of questions concerning research involving human embryonic cells.

Since pluripotent stem cells have the ability to differentiate into any type of cell, they are used in the development of medical treatments for a wide range of conditions. Treatments that have been proposed include treatment for physical trauma, degenerative conditions, and genetic diseases (in combination with gene therapy). Yet further treatments using stem cells could potentially be developed due to their ability to repair extensive tissue damage.[1]

Great levels of success and potential have been realized from research using adult stem cells. In early 2009, the FDA approved the first human clinical trials using embryonic stem cells. These can become any cell type of the body, excluding placental cells. This ability is called pluripotency. Only cells from an embryo at the morula stage or earlier are truly totipotent, meaning that they are able to form all cell types including placental cells. Adult stem cells are generally limited to differentiating into different cell types of their tissue of origin. However, some evidence suggests that adult stem cell plasticity may exist, increasing the number of cell types a given adult stem cell can become.

Many of the debates surrounding human embryonic stem cells concern issues such as what restrictions should be made on studies using these types of cells. At what point does one consider life to begin? Is it just to destroy an embryo cell if it has the potential to cure countless numbers of patients? Political leaders are debating how to regulate and fund research studies that involve the techniques used to remove the embryo cells. No clear consensus has emerged. Other recent discoveries may extinguish the need for embryonic stem cells.[2]

Much of the criticism has been a result of religious beliefs, and in the most high-profile case, Christian US President George W Bush signed an executive order banning the use of federal funding for any cell lines other than those already in existence, stating at the time, "My position on these issues is shaped by deeply held beliefs," and "I also believe human life is a sacred gift from our creator."[3] This ban was in part revoked by his successor Barack Obama, who stated "As a person of faith, I believe we are called to care for each other and work to ease human suffering. I believe we have been given the capacity and will to pursue this research and the humanity and conscience to do so responsibly." [4]

Some stem cell researchers are working to develop techniques of isolating stem cells that are as potent as embryonic stem cells, but do not require a human embryo.

Foremost among these was the discovery in August 2006 that adult cells can be reprogrammed into a pluripotent state by the introduction of four specific transcription factors, resulting in induced pluripotent stem cells.[5] This major breakthrough won a Nobel Prize for the discoverers, Shinya Yamanaka and John Gurdon.[6]

In an alternative technique, researchers at Harvard University, led by Kevin Eggan and Savitri Marajh, have transferred the nucleus of a somatic cell into an existing embryonic stem cell, thus creating a new stem cell line.[7]

Researchers at Advanced Cell Technology, led by Robert Lanza and Travis Wahl, reported the successful derivation of a stem cell line using a process similar to preimplantation genetic diagnosis, in which a single blastomere is extracted from a blastocyst.[8] At the 2007 meeting of the International Society for Stem Cell Research (ISSCR),[9] Lanza announced that his team had succeeded in producing three new stem cell lines without destroying the parent embryos. "These are the first human embryonic cell lines in existence that didn't result from the destruction of an embryo." Lanza is currently in discussions with the National Institutes of Health to determine whether the new technique sidesteps U.S. restrictions on federal funding for ES cell research.[10]

Anthony Atala of Wake Forest University says that the fluid surrounding the fetus has been found to contain stem cells that, when used correctly, "can be differentiated towards cell types such as fat, bone, muscle, blood vessel, nerve and liver cells". The extraction of this fluid is not thought to harm the fetus in any way. He hopes "that these cells will provide a valuable resource for tissue repair and for engineered organs, as well".[11]

The status of the human embryo and human embryonic stem cell research is a controversial issue, as with the present state of technology, the creation of a human embryonic stem cell line requires the destruction of a human embryo. Most of these embryos are discarded. Stem cell debates have motivated and reinvigorated the pro-life movement, whose members are concerned with the rights and status of the embryo as an early-aged human life. They believe that embryonic stem cell research instrumentalizes and violates the sanctity of life and is tantamount to murder.[12] The fundamental assertion of those who oppose embryonic stem cell research is the belief that human life is inviolable, combined with the belief that human life begins when a sperm cell fertilizes an egg cell to form a single cell. The view of those in favor is that these embryos would otherwise be discarded, and if used as stem cells, they can survive as a part of a living human being.

A portion of stem cell researchers use embryos that were created but not used in in vitro fertility treatments to derive new stem cell lines. Most of these embryos are to be destroyed, or stored for long periods of time, long past their viable storage life. In the United States alone, an estimated at least 400,000 such embryos exist.[13] This has led some opponents of abortion, such as Senator Orrin Hatch, to support human embryonic stem cell research.[14] See also embryo donation.

Medical researchers widely report that stem cell research has the potential to dramatically alter approaches to understanding and treating diseases, and to alleviate suffering. In the future, most medical researchers anticipate being able to use technologies derived from stem cell research to treat a variety of diseases and impairments. Spinal cord injuries and Parkinson's disease are two examples that have been championed by high-profile media personalities (for instance, Christopher Reeve and Michael J. Fox, who have lived with these conditions, respectively). The anticipated medical benefits of stem cell research add urgency to the debates, which has been appealed to by proponents of embryonic stem cell research.

In August 2000, The U.S. National Institutes of Health's Guidelines stated:

...research involving human pluripotent stem cells...promises new treatments and possible cures for many debilitating diseases and injuries, including Parkinson's disease, diabetes, heart disease, multiple sclerosis, burns and spinal cord injuries. The NIH believes the potential medical benefits of human pluripotent stem cell technology are compelling and worthy of pursuit in accordance with appropriate ethical standards.[15]

In 2006, researchers at Advanced Cell Technology of Worcester, Massachusetts, succeeded in obtaining stem cells from mouse embryos without destroying the embryos.[16] If this technique and its reliability are improved, it would alleviate some of the ethical concerns related to embryonic stem cell research.

Another technique announced in 2007 may also defuse the longstanding debate and controversy. Research teams in the United States and Japan have developed a simple and cost-effective method of reprogramming human skin cells to function much like embryonic stem cells by introducing artificial viruses. While extracting and cloning stem cells is complex and extremely expensive, the newly discovered method of reprogramming cells is much cheaper. However, the technique may disrupt the DNA in the new stem cells, resulting in damaged and cancerous tissue. More research will be required before noncancerous stem cells can be created.[17][18][19][20]

Update article to include 2009/2010 current stem cell usages in clinical trials.[21][22] The planned treatment trials will focus on the effects of oral lithium on neurological function in people with chronic spinal cord injury and those who have received umbilical cord blood mononuclear cell transplants to the spinal cord. The interest in these two treatments derives from recent reports indicating that umbilical cord blood stem cells may be beneficial for spinal cord injury and that lithium may promote regeneration and recovery of function after spinal cord injury. Both lithium and umbilical cord blood are widely available therapies that have long been used to treat diseases in humans.

This argument often goes hand-in-hand with the utilitarian argument, and can be presented in several forms:

This is usually presented as a counter-argument to using adult stem cells as an alternative that does not involve embryonic destruction.

This argument is used by opponents of embryonic destruction, as well as researchers specializing in adult stem cell research.

Pro-life supporters often claim that the use of adult stem cells from sources such as umbilical cord blood has consistently produced more promising results than the use of embryonic stem cells.[30] Furthermore, adult stem cell research may be able to make greater advances if less money and resources were channeled into embryonic stem cell research.[31]

In the past, it has been a necessity to research embryonic stem cells and in doing so destroy them for research to progress.[32] As a result of the research done with both embryonic and adult stem cells, new techniques may make the necessity for embryonic cell research obsolete. Because many of the restrictions placed on stem cell research have been based on moral dilemmas surrounding the use of embryonic cells, there will likely be rapid advancement in the field as the techniques that created those issues are becoming less of a necessity.[33] Many funding and research restrictions on embryonic cell research will not impact research on IPSCs (induced pluripotent stem cells) allowing for a promising portion of the field of research to continue relatively unhindered by the ethical issues of embryonic research.[34]

Adult stem cells have provided many different therapies for illnesses such as Parkinson's disease, leukemia, multiple sclerosis, lupus, sickle-cell anemia, and heart damage[35] (to date, embryonic stem cells have also been used in treatment),[36] Moreover, there have been many advances in adult stem cell research, including a recent study where pluripotent adult stem cells were manufactured from differentiated fibroblast by the addition of specific transcription factors.[37] Newly created stem cells were developed into an embryo and were integrated into newborn mouse tissues, analogous to the properties of embryonic stem cells.

Austria, Denmark, France, Germany, and Ireland do not allow the production of embryonic stem cell lines,[38] but the creation of embryonic stem cell lines is permitted in Finland, Greece, the Netherlands, Sweden, and the United Kingdom.[38]

In 1973, Roe v. Wade legalized abortion in the United States. Five years later, the first successful human in vitro fertilization resulted in the birth of Louise Brown in England. These developments prompted the federal government to create regulations barring the use of federal funds for research that experimented on human embryos. In 1995, the NIH Human Embryo Research Panel advised the administration of President Bill Clinton to permit federal funding for research on embryos left over from in vitro fertility treatments and also recommended federal funding of research on embryos specifically created for experimentation. In response to the panel's recommendations, the Clinton administration, citing moral and ethical concerns, declined to fund research on embryos created solely for research purposes,[39] but did agree to fund research on leftover embryos created by in vitro fertility treatments. At this point, the Congress intervened and passed the Dickey Amendment in 1995 (the final bill, which included the Dickey Amendment, was signed into law by Bill Clinton) which prohibited any federal funding for the Department of Health and Human Services be used for research that resulted in the destruction of an embryo regardless of the source of that embryo.

In 1998, privately funded research led to the breakthrough discovery of human embryonic stem cells (hESC). This prompted the Clinton administration to re-examine guidelines for federal funding of embryonic research. In 1999, the president's National Bioethics Advisory Commission recommended that hESC harvested from embryos discarded after in vitro fertility treatments, but not from embryos created expressly for experimentation, be eligible for federal funding. Though embryo destruction had been inevitable in the process of harvesting hESC in the past (this is no longer the case[40][41][42][43]), the Clinton administration had decided that it would be permissible under the Dickey Amendment to fund hESC research as long as such research did not itself directly cause the destruction of an embryo. Therefore, HHS issued its proposed regulation concerning hESC funding in 2001. Enactment of the new guidelines was delayed by the incoming George W. Bush administration which decided to reconsider the issue.

President Bush announced, on August 9, 2001, that federal funds, for the first time, would be made available for hESC research on currently existing embryonic stem cell lines. President Bush authorized research on existing human embryonic stem cell lines, not on human embryos under a specific, unrealistic timeline in which the stem cell lines must have been developed. However, the Bush Administration chose not to permit taxpayer funding for research on hESC cell lines not currently in existence, thus limiting federal funding to research in which "the life-and-death decision has already been made".[44] The Bush Administration's guidelines differ from the Clinton Administration guidelines which did not distinguish between currently existing and not-yet-existing hESC. Both the Bush and Clinton guidelines agree that the federal government should not fund hESC research that directly destroys embryos.

Neither Congress nor any administration has ever prohibited private funding of embryonic research. Public and private funding of research on adult and cord blood stem cells is unrestricted.

In April 2004, 206 members of Congress signed a letter urging President Bush to expand federal funding of embryonic stem cell research beyond what Bush had already supported.

In May 2005, the House of Representatives voted 238194 to loosen the limitations on federally funded embryonic stem-cell researchby allowing government-funded research on surplus frozen embryos from in vitro fertilization clinics to be used for stem cell research with the permission of donorsdespite Bush's promise to veto the bill if passed.[45] On July 29, 2005, Senate Majority Leader William H. Frist (R-TN), announced that he too favored loosening restrictions on federal funding of embryonic stem cell research.[46] On July 18, 2006, the Senate passed three different bills concerning stem cell research. The Senate passed the first bill (the Stem Cell Research Enhancement Act) 6337, which would have made it legal for the federal government to spend federal money on embryonic stem cell research that uses embryos left over from in vitro fertilization procedures.[47] On July 19, 2006 President Bush vetoed this bill. The second bill makes it illegal to create, grow, and abort fetuses for research purposes. The third bill would encourage research that would isolate pluripotent, i.e., embryonic-like, stem cells without the destruction of human embryos.

In 2005 and 2007, Congressman Ron Paul introduced the Cures Can Be Found Act,[48] with 10 cosponsors. With an income tax credit, the bill favors research upon nonembryonic stem cells obtained from placentas, umbilical cord blood, amniotic fluid, humans after birth, or unborn human offspring who died of natural causes; the bill was referred to committee. Paul argued that hESC research is outside of federal jurisdiction either to ban or to subsidize.[49]

Bush vetoed another bill, the Stem Cell Research Enhancement Act of 2007,[50] which would have amended the Public Health Service Act to provide for human embryonic stem cell research. The bill passed the Senate on April 11 by a vote of 63-34, then passed the House on June 7 by a vote of 247176. President Bush vetoed the bill on July 19, 2007.[51]

On March 9, 2009, President Obama removed the restriction on federal funding for newer stem cell lines. [52] Two days after Obama removed the restriction, the president then signed the Omnibus Appropriations Act of 2009, which still contained the long-standing Dickey-Wicker provision which bans federal funding of "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death;"[53] the Congressional provision effectively prevents federal funding being used to create new stem cell lines by many of the known methods. So, while scientists might not be free to create new lines with federal funding, President Obama's policy allows the potential of applying for such funding into research involving the hundreds of existing stem cell lines as well as any further lines created using private funds or state-level funding. The ability to apply for federal funding for stem cell lines created in the private sector is a significant expansion of options over the limits imposed by President Bush, who restricted funding to the 21 viable stem cell lines that were created before he announced his decision in 2001.[54] The ethical concerns raised during Clinton's time in office continue to restrict hESC research and dozens of stem cell lines have been excluded from funding, now by judgment of an administrative office rather than presidential or legislative discretion.[55]

In 2005, the NIH funded $607 million worth of stem cell research, of which $39 million was specifically used for hESC.[56]Sigrid Fry-Revere has argued that private organizations, not the federal government, should provide funding for stem-cell research, so that shifts in public opinion and government policy would not bring valuable scientific research to a grinding halt.[57]

In 2005, the State of California took out $3 billion in bond loans to fund embryonic stem cell research in that state.[58]

China has one of the most permissive human embryonic stem cell policies in the world. In the absence of a public controversy, human embryo stem cell research is supported by policies that allow the use of human embryos and therapeutic cloning.[59]

According to Rabbi Levi Yitzchak Halperin of the Institute for Science and Jewish Law in Jerusalem, embryonic stem cell research is permitted so long as it has not been implanted in the womb. Not only is it permitted, but research is encouraged, rather than wasting it.

However in order to remove all doubt [as to the permissibility of destroying it], it is preferable not to destroy the pre-embryo unless it will otherwise not be implanted in the woman who gave the eggs (either because there are many fertilized eggs, or because one of the parties refuses to go on with the procedurethe husband or wifeor for any other reason). Certainly it should not be implanted into another woman.... The best and worthiest solution is to use it for life-saving purposes, such as for the treatment of people that suffered trauma to their nervous system, etc.

Similarly, the sole Jewish majority state, Israel, permits research on embryonic stem cells.

The Catholic Church opposes human embryonic stem cell research calling it "an absolutely unacceptable act." The Church supports research that involves stem cells from adult tissues and the umbilical cord, as it "involves no harm to human beings at any state of development."[60]

The Southern Baptist Convention opposes human embryonic stem cell research on the grounds that "Bible teaches that human beings are made in the image and likeness of God (Gen. 1:27; 9:6) and protectable human life begins at fertilization."[61] However, it supports adult stem cell research as it does "not require the destruction of embryos."[61]

The United Methodist Church opposes human embryonic stem cell research, saying, "a human embryo, even at its earliest stages, commands our reverence."[62] However, it supports adult stem cell research, stating that there are "few moral questions" raised by this issue.[62]

The Assemblies of God opposes human embryonic stem cell research, saying, it "perpetuates the evil of abortion and should be prohibited."[63]

The religion of Islam favors the stance that scientific research and development in terms of stem cell research is allowed as long as it benefits society while using the least amount of harm to the subjects. "Stem cell research is one of the most controversial topics of our time period and has raised many religious and ethical questions regarding the research being done. With there being no true guidelines set forth in the Qur'an against the study of biomedical testing, Muslims have adopted any new studies as long as the studies do not contradict another teaching in the Qur'an. One of the teachings of the Qur'an states that Whosoever saves the life of one, it shall be if he saves the life of humankind (5:32), it is this teaching that makes stem cell research acceptable in the Muslim faith because of its promise of potential medical breakthrough."[64]

The First Presidency of The Church of Jesus Christ of Latter-day Saints "has not taken a position regarding the use of embryonic stem cells for research purposes. The absence of a position should not be interpreted as support for or opposition to any other statement made by Church members, whether they are for or against embryonic stem cell research.[65]

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Stem cell controversy - Wikipedia

Future of Stem Cell Research – Creating New organs and …

Written by Patrick Dixon

Futurist Keynote Speaker: Posts, Slides, Videos - Biotechnology, Genetics, Gene Therapy, Stem Cells

Stem cell research. Embryonic stem cells and adult stem cells - biotech company progress, stem cell investment, stem cell research results, should you invest in stem cell technology, stem cell organ repair and organ regeneration? Treatment using adult stem cells for people like the late Christopher Reeves, with recent spinal cord injuries - or stroke, or heart damage.

Comment by Dr Patrick Dixon on stem cell research and science of ageing, health care, life expectancy, medical advances, pensions, retirement, lifestyles. (ReadFREE SAMPLE of The Truth about Almost Everything- his latest book.)

Every week there are new claims being made about embryonic stem cells and adult stem cells, what is the truth? Scientific facts have often been lost in the media debate. The death of Superman hero Christopher Reeves has also focussed attention on stem cell research, and the urgent needs of those with spinal cord injury.

Here is a brief summary of important stem cell trends. You will also find on this site keynote presentations on stem cell research, speeches and powerpoint slides on the future of health care, the future of medicine, the future of the pharmaceutical industry, and the future of ageing - all of which are profoundly impacted by stem cell research.

There is no doubt that we are on the edge of a major stem cell breakthrough. Stem cells will one day provide effective low-cost treatment for diabetes, some forms of blindness, heart attack, stroke, spinal cord damage and many other health problems. Animal stem cell studies are already very promising and some clinical trials using stem cells have started (article written in September 2004).

As a physician and a futurist I have been monitoring the future of stem cells for over two decades and advise corporations on these issues. Stem cell investment, research effort, and treatment focus is moving rapidly away from embryonic stem cells (ethical and technical challenges) to adult stem cells which are turning out to be far easier to convert into different tissues than we thought.

I have met a number of leading researchers, and their progress in stem cell research is now astonishing, while over 2,000 new research papers on embryonic or adult stem cells are published in reputable scientific journals every year.

Stem cell technology is developing so fast that many stem cell scientists are unaware of important progress by others in their own or closely related fields. They are unable to keep up. The most interesting work is often unpublished, or waiting to be published. There is also of course commercial and reputational rivalry, which can on occasions tempt scientists to downplay the significance of other people's results (or their claims).What exactly are stem cells? Will stem cells deliver? Should you invest in biotech companies that are developing stem cell technology? What should physicians, health care professionals, planners and health departments expect? What will be the impact of stem cell treatments on the pharmaceutical industry? How expensive will stem cell treatments be? What about the ban on embryonic stem cell research in many nations? Do embryonic stem cell treatments have a future or will they be overtaken by adult stem cell technology?

Embryonic stem cells are also hard to control, and hard to grow in a reliable way. They have "minds" of their own, and embryonic stem cells are often unstable, producing unexpected results as they divide, or even cancerous growths. Human embryonic stem cells usually cause an immune reaction when transplanted into people, which means cells used in treatment may be rapidly destroyed unless they are protected, perhaps by giving medication to suppress the immune system (which carries risks).

One reason for intense interest in human cloning technology is so-called therapeutic cloning. This involves combining an adult human cell with a human egg from which the nucleus has been removed. The result is a human embryo which is dividing rapidly to try and become an identical twin of the cloned adult. If implanted in the womb, such cloned embryos have the potential to be born normally as cloned babies, although there are many problems to overcome, including catastrophic malformations and premature ageing as seen in animals such as Dolly the sheep.

In theory, therapeutic cloning could allow scientists to take embryonic stem cells from the cloned embryo, throw the rest of the embryo away and use the stem cells to generate new tissue which is genetically identical to the person cloned. In practice, this is a very expensive approach fraught with technical challenges as well as ethical questions and legal challenges.

An alternative is to try to create a vast tissue bank of tens of thousands of embryonic cells lines, by extracting stem cells from so many different human embryos that whoever needs treatment can be closely matched with the tissue type of an existing cell line. But even if this is achieved, problems of control and cancer remain. And again there are many ethical considerations with any science that uses human embryos, each of which is an early developing but complete potential human being, which is why so many countries have banned this work.

However a moment's thought tells us how illogical such a view was, and indeed we are now finding that many cells in children and adults have extraordinary capacity to generate or stimulate growth of a wide variety of tissues, if encouraged in the right way.

Take for example the work of Professor Jonathan Slack at Bath University who has shown how adult human liver cells can be transformed relatively easily into insulin producing cells such as those found in the pancreas, or the work of others using bone marrow cells to repair brain and spinal cord injuries in mice and rats, and now doing the same to repair heart muscle in humans.

Why should this surprise us? We know that almost all cells in your body contain your entire genome or book of life: enough information to make an entire copy of you, which is the basis of cloning technology. So in theory, just about every cell can make any tissue you need. However, the reality is that in most cells almost every gene you have is turned off - but as it turns out, not as permanently as we thought.

If we take one of your skin cells and fuse it with an unfertilized human egg, the chemical bath inside a human egg activates all the silenced genes, and the combined cell becomes so totipotent that it starts to make a new human being.

What then if we could find a way to reactivate just a few silenced genes, and perhaps at the same time silence some of the others? Could we find a chemical that would mimic what happens in the embryo, with the power to transform cells from one type into another? Yes we can. Jonathan Slack and others have done just that. What was considered impossible five years ago is already history.

Could we take adult cells and force them back into a more general, undetermined embryonic state? Yes we can. It is now possible to create cells with a wide range of plasticity, all from adult tissue. The secret is to get the right gene activators into the nucleus, not so hard as we thought.

Suppose you have a heart attack. A cardiothoracic surgeon talks to you about using your own stem cells in an experimental treatment. You agree. A sample of bone marrow is taken from your hips, and processed using standard equipment found in most oncology centers for treating leukemia. The result is a concentrated number of special bone marrow cells, which are then injected back into your own body - either into a vein in your arm, or perhaps direct into the heart itself.

The surgeon is returning your own unaltered stem cells back to you, to whom these cells legally belong. This is not a new molecule requiring years of animal and clinical tests. Your own adult stem cells are available right now. No factory is involved - nor any pharmaceutical company sales team.

What is more, there are no ethical questions (unlike embryonic stem cells), no risk of tissue rejection, no risk of cancer.

Now we begin to see why research funds are moving so fast from embryonic stem cells to adult alternatives.

Harvard Medical School is another center of astonishing progress in adult stem cells. Trials have shown partially restored sight in animals with retinal damage. Clinical trials are expected within five years, using adult stem cells as a treatment to cure blindness caused by macular degeneration - old-age blindness and the commonest cause of sight-loss in America. Within 10 years, it is hoped that people will be able to be treated routinely with their own stem cells in a clinic using a two-hour process.

If you want further evidence of this switch in interest from embryonic to adult stem cells, look at the makers of Dolly the sheep. The Rosslyn Institute in Scotland are pioneers in cloning technology. They, along with others, campaigned successfully in UK Parliament for the legal right to use the same technology in human embryos (therapeutic cloning, not with the aim of clones being born). But three years later, they had not even bothered to apply for a human cloning licence.

Why not? Because investors were worried about throwing money at speculative embryo research with massive ethical and reputational risks. Newcastle University made headlines in August 2004 when granted the first licence to clone human embryos - but the real story was why it had taken so long to get a single research institute in the UK to actually get on and apply. Answer: medical research moved on and left the "therapeutic" human cloners behind.

The debate centers on technical questions and semantics, rather than the reality of results. Take for example heart repair. We know that bone marrow cells can land up in damaged heart and when present, the heart is repaired. It is hard to be certain what proportion of this remarkable process is due to stimulants released locally by bone marrow cells, or by the bone marrow cells actually differentiating into heart tissue.

It remains a confusing picture, not least because in the lab, cells seem to change character profoundly, but in clinical trials it appears the effects of many stem cells are stimulatory. But who cares? As a clinician, I am delighted if injecting your bone marrow cells into your back means that you are walking around 3 months after a terrible injury to your spine instead of being in a wheelchair for the rest of your life. I am not so concerned with exactly how it all works, and nor will you be.

In summary, expect rapid progress in adult stem cells and slower, less intense work with embryonic stem cells. Embryonic stem cell technology is already looking rather last-century, along with therapeutic cloning. History will show that, by 2020, we were already able to produce a wide range of tissues using adult stem cells, with spectacular progress in tissue building and repair. In some cases, these stem cells will be actually incorporated into the new repairs as differentiated cells, in other cases, they will be temporary assistants in local repair processes.

And along the way we will see a number of biotech companies fold, as a result of over-investment into embryonic stem cells, plus angst over ethics and image, without watching the radar screen closely enough, failing to see the onward march of adult stem cell technology.

Using embryos as a source of spare-part cells will always be far more controversial than using adult tissue, or perhaps cells from umbilical cord after birth, and investors will wish to reduce uneccessary risk, both to the projects they fund, and to their own organisations by association.

Despite this, we can expect embryonic stem cell research to continue in some countries, with the hope of scientific breakthroughs of various kinds.

Article written May 2004.

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Bipolar Cell Pathways in the Vertebrate Retina by Ralph …

Ralph Nelson and Victoria Connaughton

1. Introduction.

Retinal ganglion cells are typically only two synapses distant from retinal photoreceptors, yet ganglion cell responses are far more diverse than those of photoreceptors. The most direct pathway from photoreceptors to ganglion cells is through retinal bipolar cells. Thus, it is of great interest to understand how bipolar cells transform visual signals.

Werblin and Dowling (1) were among the first to investigate light-evoked responses of retinal bipolar cells. Based on these studies using penetrating microelectrodes, they proposed that retinal bipolar cells lacked impulse activity, and that they processed visual signals through integration of analogue signals, that is synaptic currents and non-spike-generating voltage-gated membrane currents.

Frank Werblin and John Dowling discovered the ON or OFF light-evoked physiology of retinal bipolar cells (1). They characterized these neurons as processors of analogue visual signals that did not use impulse generation. The work was done at Johns Hopkins University as a part of Frank Werblins doctoral dissertation under John Dowlings mentorship.

Werblin and Dowing also proposed that retinal bipolar cells come in two fundamental varieties: ON-center and OFF-center (Fig. 1). Both types displayed a surround region in their receptive field that opposed the center, similar to the classic, antagonistic center-surround organization earlier described for ganglion-cell receptive fields (2). Ganglion cell receptive field organization is further reviewed in the Webvision chapter on ganglion cells. ON-center bipolar cells are depolarized by small spot stimuli positioned in the receptive field center. OFF-center bipolar cells are hyperpolarized by the same stimuli. Both types are repolarized by light stimulation of the peripheral receptive field outside the center (Fig. 1). Bipolar cells with ON-OFF responses were not encountered (1). ON-OFF responses, excitation at both stimulus onset and offset, first occur among amacrine cells, neurons postsynaptic to bipolar cells.

The Werblin and Dowling characterization of bipolar-cell physiology has proved quite durable over many decades. The notion that bipolar cells do not spike has found exception for some bipolar types. Dark-adapted Mb1 (rod bipolar cells) of goldfish generate light-evoked calcium spikes. These spikes originate in bipolar-cell axon terminals (3, 4). Through genetic imaging techniques this finding has been extended to the axon terminals of many zebrafish bipolar-cell types. In these studies bipolar terminals were labeled transgenically with the Ca2+ reporter protein SyGCaMP2 and light-induced fluctuations in Ca2+ were followed by 2-photon photometry. Fully 65% of the terminals delivered a spiking Ca2+ signal (4). In the cb5b bipolar-cell type of ground squirrel retina Na+ action potentials are driven by light. Other bipolar types in this retina do not exhibit spiking (5). These results suggest that bipolar cells are responsible for significantly more of the encoding of visual signals than had been previously supposed, and that axon-terminal spiking is actively involved. Impulse generation in bipolar cells is further discussed in the section on Voltage-gated currents.

Figure 1. Retinal bipolar cells initiate ON and OFF pathways. Microelectrode recordings of voltage responses from mudpuppy retinal neurons reveal two sorts of retinal bipolar cells: those hyperpolarized by central illumination (OFF Bipolar Cell) and those depolarized by central illumination (ON Bipolar Cell). In each case membrane potential is restored by concomitant illumination of annular rings surrounding the center. Such responses are typically 10 mV in amplitude and lack impulse activity. The absolute response latency to the light step above is about 100 msec for these suprathreshold stimuli. The illustration is taken from Werblin and Dowling, 1969 (1).

Morphology and connectivity

Anatomical investigations of bipolar cells reveal a multiplicity (4-22 depending on species) of different morphological types (6-12), significantly more than the just two types that early physiology implied. The diversity of human retinal bipolar types is illustrated in Fig. 2. Nonetheless all of these are either ON- or OFF-types and their diversity results from other factors, such as differing connectivity with photoreceptors and differing postsynaptic targets, as evidenced in the diversity of dendritic and axon-terminal ramification patterns. Some bipolar cells are postsynaptic only to rods, others only to cones (Fig. 2), and still others receive mixed rod-cone input. Among cone-selective bipolar cells, some innervate only red, green, or blue cones, while others are diffuse, that is, not selective (13-19). Different bipolar types express different glutamate receptors at subsynaptic contacts with cones.

Bipolar cell axon terminals are either mono- or multistratified, depending on the location of axonal boutons and branches in the inner plexiform layer (IPL). Differing terminal position and branching morphology within the IPL suggests that different morphological types selectively innervate different types of amacrine and ganglion cell (Fig 2).In primate retinas, bipolar cells are described as diffuse or midget types, based on the extent of the dendritic arbor. Midgets contact only a single cone, while diffuse types contact multiple cones. Bipolar cells are also termed flat or invaginating (20) depending on the placement of dendritic tips, either on the surface of (flat), or penetrating within photoreceptor synaptic terminals to approach presynaptic ribbons (invaginating).Fig. 2 illustrates 11 morphological types of bipolar cell seen in Golgi-stained human retinas.

Figure 2. Dendritic and axonal stratification patterns of bipolar cell types in human retina. The illustration is courtesy of Helga Kolb.

Bipolar cell axon terminals are either mono- or multistratified, depending on the location of axonal boutons and branches in the inner plexiform layer (IPL). Differing terminal position and branching morphology within the IPL suggests that different morphological types selectively innervate different types of amacrine and ganglion cell (Fig 2).In primate retinas, bipolar cells are described as diffuse or midget types, based on the extent of the dendritic arbor. Midgets contact only a single cone, while diffuse types contact multiple cones. Bipolar cells are also termed flat or invaginating (20) depending on the placement of dendritic tips, either on the surface of (flat), or penetrating within photoreceptor synaptic terminals to approach presynaptic ribbons (invaginating).Fig. 2 illustrates 11 morphological types of bipolar cell seen in Golgi-stained human retinas.

2. Different glutamate receptor types for ON and OFF bipolar cells.

Light responses in bipolar cells are initiated by synapses with photoreceptors. Photoreceptors release only one neurotransmitter, glutamate (21); yet bipolar cells react to this stimulus with two different responses, ON-center (glutamate hyperpolarization) and OFF-center (glutamate depolarization). Different postsynaptic glutamate receptor proteins mediate these different membrane polarizing mechanisms. The different glutamate-gated responses are associated with the differential expression of either ionotropic (iGluR) glutamate receptors (OFF bipolar cells), metabotropic (mGluR) glutamate receptor types (ON bipolar cells) or glutamate transporters (ON bipolar cells). As a result, signal transduction at the photoreceptor-to-bipolar synapse has a range of properties. The process of splitting images into multiple components tuned to selective visual features begins with differentiation of different photoreceptor types but is then greatly elaborated at the synapses between photoreceptors and bipolar cells.

Metabotropic responses of ON bipolar cells: mGluR6, Go, TRPM1, Nyctalopin

The conductance of ON bipolar cells increases in the light, whereas OFF bipolar cell conductance decreases (22, 23). The decrease in OFF bipolar cell conductance is easily explained as a loss of excitation by glutamate, as light inhibits glutamate release from photoreceptors (24). The positive reversal potential of the ON bipolar cell light response, coupled with a conductance increase (22, 25), implies that glutamate blocks a cation-permeable channel. Originally a puzzle, this was the first evidence of what we now understand as the action of metabotropic glutamate receptors (mGluRs). These receptors do not form ion channels themselves, but act as isolated antennae on the cell surface sensing glutamate and activating intracellular pathways, ultimately affecting membrane potential through mechanisms several steps removed from the binding site for glutamate. Metabotropic receptors have been identified on the axon terminals of both photoreceptors (26) and bipolar cells (27) where they serve as autoreceptors regulating glutamate release. However, the expression of one specific mGluR in the subsynaptic membrane of ON bipolar cell dendrites, the APB receptor, is unique to retina, where it is used in the direct signal transmission pathway from photoreceptors to ON bipolar cells.

Figure 3. Metabotropic glutamate receptors in the ON pathway. The glutamate agonist 2-Amino-4-Phosphonobutric acid (APB, later termed DL-AP4) interferes with light responses and membrane physiology of ON-center bipolar cells in mudpuppy. A. APB abolishes light responses (the rectangular depolarizing events), hyperpolarizes the membrane potential, and increases the membrane resistance. The latter is measured by the amplitude of voltage responses to injected current pulses (arrow). B. 3 mM cobalt, a blocker for synaptic release of glutamate from photoreceptors, abolishes light responses in an ON bipolar cell and depolarizes the membrane potential. The membrane potential can be later restored by application of APB, which acts as a substitute for the missing photoreceptor glutamate. As APB is selective for a subset of metabotropic glutamate receptors, synaptic transmission of light responses to ON bipolar cells must rely on a metabotropic mechanism. The illustration is adapted from Slaughter and Miller, 1981 (28).

The mGluR6 receptor

Slaughter and Miller (28) were the first to observe that the metabotropic glutamate agonist 2-amino-4-phosphonobutric acid (APB or DL-AP4, with the L enantiomer being effective) completely blocks the light responses of ON bipolar cells. In these neurons, APB acts as a substitute for photoreceptor-released glutamate (Fig. 3AB). Thus, ON bipolar cells utilize a metabotropic pathway to sense light-induced variations in release of photoreceptor glutamate. The metabotropic receptor has been identified as mGluR6 (29, 30). Transgenic knockout mice lacking the mGluR6 gene lack the electroretinographic b-wave (Fig. 4AB), an evoked-potential component associated with ON bipolar activity (31). The relation of electroretinogram components to cellular electrophysiology is further discussed in the Webvision chapter The Electroretinogram: ERG. Immunocytochemical localization for mGluR6 shows staining in the invaginating dendritic tips of monkey bipolar cells (Fig. 5) (32). Invaginating bipolar cells are thought to be mainly ON types in primate retina. Some foveal flat contacts also stained for mGluR6 (32).

Figure 4. MGluR6 is the metabotropic glutamate receptor expressed by ON bipolar cells. Light evoked ERG responses from the eye of a wild type (A, +/+) and a mutant (B, -/-) mouse deficient in the gene encoding mGluR6. The b-wave, which originates from the light responses of ON bipolar cells is absent in the mutant mouse. The illustration is adapted from Masu et al, 1995 (31).

Figure 5. Immunostaining for the metabotropic glutamate receptor mGluR6 selectively labels dendritic tips of invaginating bipolar cells (ib) in monkey retina. The adjacent dendritic contacts from horizontal cells (h) and the flat contact (f) from a flat cone bipolar cell are not labeled, nor is the presynaptic cone pedicle (c).The illustration is from Vardi et al., 1998 (33).

The G-protein Go

In addition to mGluR6, the G-protein Go is cytoplasmically localized in the dendritic tips of ON bipolar cells (Fig. 6) (33). Removal of the alpha subunit (Go) by knockout results in b-wave loss (34), similar to the mGluR6 knockout. Go was originally localized in rod bipolar cells, known to be ON-type, in a screen of potential G-protein second messengers for the metabotropic light response (35). This suggests that Go is directly involved in the intracellular pathway following mGluR6 activation.

The ion channel coupled to the APB receptor was originally thought to be cGMP-modulated (36).The closure of ion channels following APB binding onto mGluR6 seemed to require GTP and phosphodiesterase similar to phototransduction (36). However, the exact cascade by which this happened was less clear, as blocking phosphodiesterase (PDE) activity, or adding non-hydrolyzable cGMP analogs, did not inhibit the glutamate responses generated through APB-receptors (37). Further, it was Go that suppressed glutamate-gated current in ON bipolar cells, not transducin, the G-protein of the phototransduction cascade (37). Thus, removal of cGMP appears not to be required for channel closure (37).

Figure 6. Immunostaining for Go, the the alpha subunit of the G-protein Go, localizes to the invaginating dendritic tips of a rod bipolar cell (left) and a cone bipolar cell (right) in cat retina. Go is required for light activation of ON bipolar cells. The illustration is from Vardi, 1998 (33).

The TRPM1 channel

In agreement with these findings, recent work suggests the ON-bipolar-cell ion channel downstream of the mGluR6 receptor is not cGMP-gated (38). Rather, this non-selective cation channel identified as a TRPM1-L channel appears to be regulated by Go (38-40) in conjunction with G (41). The activity of the TRPM1 channel requires the presence of mGluR6, as the channel, though present, can not be activated in mGluR6 knockout mice (42).

TRP channels, or transient receptor potential channels, first identified in Drosophila photoreceptors (43), are present in all animal groups, including vertebrates (44), and as many as 28 channel subtypes have been identified. The TRP superfamily includes 7 subfamilies separated into two groups: TRPC, TRPV, TRPM, TRPN, and TRPA channels form Group 1; TRPP and TRPML channels form Group 2. TRPM1-L or melastatin, a melanoma related TRP channel, belongs to Group 1, and is found in ON bipolar cells. All channels share structural similarities and are permeable to cations; however, there is great functional diversity among the different channel subtypes. TRP channels are involved in many sensory systems including vision, hearing, taste, temperature-sensitivity, and osmoregulation, and are also involved in human disease (44-48).

Figure 7. TRPM1 channel knockouts lack photoresponses in ON-bipolar cells. A. In a wild type mouse, antibody staining for TRPM1 reveals localization in bipolar cells. No antibody staining is evident in the knockout. B. ON-bipolar-cell patch recordings in wild type mice reveal inward currents in response to light stimulation. This is the normal response of an ON-type bipolar cell as these cells are excited by light. No inward currents occur in ON-bipolar-cell recordings from the knockout. The illustrations are from Koike et al, 2010 (38).

In retina, TRP channels have been identified on photoreceptors (49), amacrine cells (50, 51), and ON-type bipolar cells. ON-bipolars (Fig. 7A), specifically, are antigenic for TRPM1 channels (52, 53) or TRPM1-L (38, 39, 54). Immunocytochemical and/orin situhybridization studies have localized TRPM1 expression to the dendritic tips of ON-bipolar cells (38, 39, 52), though labeling is seen in cell bodies and axons as well (Fig. 7A). TRP channels are absent in OFF-type bipolar cells. TRPM1-L channel currents have a reversal potential ~0mV (38) similar to the reversal potential of glutamate-gated currents in these cells. TRPM1-L has been shown to co-localize with and/or be functionally coupled to mGluR6 (38, 40, 42, 52). In transfected CHO cells that express mGluR6, Go, and TRPM1-L, Koike and colleagues (38) showed that all three of these components must be present for glutamate-evoked whole-cell currents to be recorded. Cells expressing only mGluR6 and Go,or only Goand TRPM1-L, did not respond to glutamate application (38, 39). These findings suggest TRPM1 channels are downstream of the mGluR6 receptor and are necessary for glutamate-elicited responses in these cells. Further, TRPM1 -/- knockout mice (Fig. 7B) do not have light-evoked ON-bipolar-cell responses and there is no ERG b-wave (38, 39, 55). The loss of response is similar to that reported for mGluR6 -/- mice (Fig. 4) (31, 56), again suggesting that both mGluR6 and TRPM1 channels are required for ON-bipolar-cell photic responses. While all cone bipolar cells in mouse appear to use an mGluR6 synapse with cones, there is evidence that some of these cells may modulate a cation channel in addition to TRPM1-L. In the TRPM1 -/- mouse, the mGluR6 antagonist CPPG still blocks a minor APB-induced membrane current (52).

Figure 8a. The insertion of the fusion protein EYFP-nyctalopin into nob NYX -/- mice re-establishes nyctalpin expression. Expression can be localized with EYFP antibodies. A. DIC image of mouse retinal slice. OS, outer segments; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GC, ganglion cell layer. B. Wild type mouse is not labeled by anti-GFP. C. EYFP-NYX rescue mouse shows fusion protein localization in bipolar-cell dendritic tips within the OPL. D. High magnification of C. E. peanut agglutinin reaction labels cone terminals. F. Overlay of D and E shows NYX expression (nyctalpin) is localized in cone terminals (yellow). Green localization is presumed in rod terminals. Scale bar in A, B and C is 50 m. The illustration is from Gregg et al, 2007 (57).

The proteoglycan nyctalopin

Nyctalopin is another protein expressed on the dendritic tips of ON-bipolar cells (Fig. 8a). It is encoded by the NYX gene. NYX is required for light- and glutamate-elicited responses in ON bipolar cells (57). Mutant nob mice (58) lack an ERG b-wave and are not responsive to focal applications of glutamate onto the bipolar cell dendritic arbor (57). In wild type mice ON bipolar cells respond with outward currents to this treatment, but in nob mice they do not (Fig. 9). The nob strain is an NYX -/- mutant (59). Generation of transgenic nob mice selectively expressing EYFP-nyctalopin fusion protein in bipolar cells completely rescued the mutant phenotype. Cellular expression was restricted to bipolar cells using a regulatory sequence for GABAc1, a GABA receptor subunit selectively produced by bipolar cells. In the EYFP-NYX line, the fusion protein expression was localized to the tips of ON-bipolar cells (Fig. 8a), the b-wave was restored, and inner retinal function was similar to controls (57).

Figure 8b. Morphology of zebrafish retinal neurons expressing nyctalopin. The transgenic strain contains an MYFP gene driven by the regulatory sequence for NYX (nyctalopin). A-D retinas from 3-day post fertilization (3 dpf) larvae show only bipolar cells, with a broad distribution of axonal filopodia within the inner plexiform layer (IPL). E-G. By 6 dpf the filopdial pattern of bipolar cell axons is restricted to the inner half of the IPL, a characteristic of ON bipolar morphology. The illustration is from Schroeter, Wong and Gregg, 2006 (60).

In zebrafish a membrane-targeted yellow fluorescent protein (MYFP) reporter strain has been generated using the upstream regulatory sequences for the NYX gene to express MYFP. This reporter marks a subset of ON-type bipolar cells with characteristic long axons and terminal boutons restricted to the inner half of the inner plexiform layer. Many of these also express the ON-bipolar marker protein kinase C (PKC) (60). This genetic reporter shows the complete morphology of the cells expressing the nyctalopin gene. This transgenic tool was used to follow embryonic refinement and development of axonal projection patterns for nyctalopin-expressing ON bipolars (60) (Fig. 8b).

Subsequent studies have reported that nyctalopin complexes with both mGluR6 and TRPM1 channels in ON-bipolar cells, serving a structural role that allows proper assembly and organization of the receptor and the channel (61). In addition, nyctalopin is able to modulate TRPM1 channels, as is mGluR6 (42, 62). Thus, glutamate binding onto mGluR6 activates a G-protein (Go and/or G) leading to the closure of TRPM1 channels. The receptor and the channel are held in close proximity by nyctalopin. Alteration or mutation of any of these components mGluR6, nyctalopin, TRPM1, and/or Go can lead to a loss of response by ON-bipolar cells. In agreement with this, individuals with congenital stationary night blindness (CSNB discussed below) display a loss of ON-bipolar cell responses as evidenced in an absent ERG b-wave, and mutations in the genes encoding mGluR6, nyctalpin, and TRPM1 are associated with at least 75% of CSNB cases (62).

Figure 9. Bipolar-cell glutamate responses in the nob (nyctalopin) knockout mouse. Patch recordings of glutamate-responses reveal outward, metobotropic glutamate, currents in both rod bipolar cells and ON-type cone bipolar cells (DBC) in control mice. No glutamate currents are recorded for these cell types in nob mice. OFF cone bipolar cells (HBC) respond with inward AMPA/kainate currents in both control and nob mice. The holding potential was -60 mV. Glutamate puffs are 100 msec from pipettes filled with 1-5mM glutamate. The illustration is from Gregg et al, 2007 (57).

Modulators and subtypes

Calcium ions are a modulator of the ON bipolar metabotropic ion channel. Calcium ions, entering through the TRPM1 ion channel (63, 64) affect channel function, either by directly down regulating the channel (63) or by activating calcium-dependent enzymes, such as CaMKII (65-67), which modulate ion channel conductance. cGMP has been shown to selectively enhance ON bipolar cell responses to dim light, and may play a modulatory role for the TRPM1 channel (68).

Metabotropic receptors for ON-center bipolar cells have sustained and transient subtypes (69). The molecular basis is not yet known. However, it appears that the sustained and transient responses of ON-center ganglion cells, such as the classic X- and Y-types (70), may have their origin, at least in part, in the type of glutamate receptor expressed on the bipolar cells which innervate them (71).

Glutamate transporter mediated responses of ON bipolar cells

Ionotropic glutamate receptors with transporter-like properties are also present on some ON-center bipolar-cell dendrites. When photoreceptor glutamate binds to these transporters, a Cl conductance forms and hyperpolarizes the cells in the dark (Fig. 10). Release from this Cl inhibition occurs in the light with the decrease in glutamate released from photoreceptors. This allows the bipolar cells to depolarize (Fig. 10). Like transporters, this glutamate-gated Cl mechanism requires [Na+]o in order to function. Thus far this mechanism has been found as a dendritic glutamate receptor only in cyprinid ON bipolar cells (72-74), though it is reported in turtle, salamander and mouse photoreceptors (75-78) and is also present in mammalian central nervous system (79). Interestingly it occurs on the axon terminals of mouse rod and cone bipolar cells, where it acts to regulate glutamate release through inhibitory feedback (78).

Figure 10. An alternate ON-bipolar synaptic mechanism is a glutamate-activated-chloride channel. Puffs of glutamate mimic photoreceptor dark release in patch recordings from bipolar cells in a zebrafish retinal slice. A. Glutamate-evoked currents are outwards for physiological ranges of membrane potential, which are positive to ECl (Cl reversal potential). They are inwards at more negative potentials. The results are consistent with an ON-center mechanism driven by changes in Cl conductance. B. The 63 mV reversal potential is consistent with a model where photoreceptor glutamate opens Cl channels. Glutamate gated Cl currents are called Iglu (73) and result from the binding of glutamate to excitatory amino acid (EAAT) transporters. The illustration is from Connaughton and Nelson, 2000 (72).

Some non-mammalian bipolar cells contain both the APB and the ionotropic (transporter-like) receptor on their dendrites, while other ON-cells express either the metabotropic or the ionotropic receptor but not both (72, 73). EAAT5 has been identified as the chloride-channel-forming glutamate transporter (80). The ionotropic mechanism is used for sustained transmission between cones and bipolar cells (81, 82), and is likely to be a fast mechanism as compared to metabotropic pathways, which involve multi-step intracellular pathways and are often relatively slow (22).

The classic Mb rod bipolar cell of fish makes synapses with both rods and cones. The rod synapse mediates a conductance increase with reversal potential positive to resting potential. The cone synapse mediates a conductance decrease with reversal potential negative to the resting potential (82). Both mechanisms provide ON-type photic responses. In retrospect it would appear that the rod synapse is metabotropic, while the cone synapse is transporter-like, two different, selectively directed post-synaptic glutamate mechanisms on the same neuron.

AMPA kainate receptor expression in ON bipolar cells

ON-center bipolar cells of mammals are immunoreactive for ionotropic AMPA receptors as well as metabotropic mGluR6 receptors (83-85). In figure 11 (right panel) immunoreactivity for GluR2/3, an ionotropic AMPA subunit, appears at an invaginating, ON-type ribbon contact in cat. Similarly in teleost retinas, ON-center bipolar cells are immunoreactive for ionotropic kainate receptors (86, 87). Particularly in mammals, no physiological role has been suggested for these conventional ionotropic receptors, usually associated with OFF bipolar cells, but also seen in ON-center bipolar cells. In giant danio Wong and Dowling find that bistratified cone bipolar cells mix ON-type and OFF-type glutamate receptor mechanisms, and utilize both transporter-like receptors and AMPA/kainate receptors in generating ON and OFF color responses respectively to different spectral stimuli (88).

Figure 11.Immunostaining for the ionotropic glutamate receptor GluR1 in bipolar cell dendrites contacting cone pedicles in cat retina. Red arrows point to flat contacts, the black arrow points to an invaginating contact, and the arrowheads point to synaptic ribbons in the cone pedicle. The illustration is from Qin and Pourcho, 1999 (261).

Figure 12. Immunostaining for ionotropic glutamate receptors in the dendritic tips of cat bipolar cells. GluR6/7 subunits are found in kainate receptors. GluR2/3 subunits are found in AMPA receptors. The red arrow (left, GluR6/7) points to a immuno-stained flat contact. The red arrow (right, GluR2/3) points to an immuno-stained invaginating contact. Letter labels are invaginating bipolar (ib), horizontal cell lateral element (h), and rod (r). The illustration is from Vardi et al., 1998 (83).

Ionotropic glutamate responses of OFF bipolar cells

Like ON bipolar cells, OFF bipolar cells express more than one type of glutamate receptor, though all are ionotropic. There are three principal types of ionotropic glutamate receptors (AMPA, kainate, and NMDA) as originally defined by agonist selectivity. Though immunocytochemical studies (84, 89, 90) and in situ hybridization (91) have identified specific NMDA receptor subunits in the outer retina, OFF bipolar cells have never been observed to utilize NMDA receptors in the generation of light responses. OFF bipolar cells selectively express either AMPA or kainate receptors (92, 93). These receptors resensitize at different rates after exposure to glutamate (Fig. 13), and as a result, emphasize different temporal characteristics of the light signal. Kainate-type glutamate receptors transfer the sustained characteristics of the visual stimulus. AMPA receptors are more selective for the transient components of the signal (92). In ground squirrel retina bipolar cells are selective for one or the other (93). The situation is interesting in so far as neurons using kainate receptors exclusively are rare in the central nervous system. Nonetheless, AMPA and kainate receptors on retinal bipolar cells are pharmacologically well-behaved. Bipolar-cell AMPA-type responses can be selectively suppressed by the lipophilic AMPA receptor antagonist GYKI 52466 (94). Conversely, bipolar-cell kainate-type responses are blocked by the desensitizing kainate receptor agonist SYM 2081 (95).

Figure 13. Different OFF bipolar cells re-sensitize at different rates after glutamate treatment. In whole cell patch recordings from ground squirrel retina, bipolar cells b3 and b2 are desensitized by an initial glutamate pulse (0). The time course of recovery is measured by responses to a second pulse after different delays. Type b3 (Fig. 16) bipolar cells utilize kainate-type glutamate receptors and require several seconds for complete recovery. Type b2 bipolar cells (Fig. 16) utilize AMPA-type glutamate receptors and recover 100 times faster. The illustration is from DeVries, 2000 (92, 93).

While all retinas contain ON and OFF bipolar cell pathways, it is easy to imagine that among these pathways natural selection might cause a divergence in the expression of dendritic glutamate receptor types depending on the visual requirements of the species. In agreement with this hypothesis, species-specific differences between ON and OFF bipolar cell dendritic glutamate responses have been found. For example, ionotropic glutamate channels with transporter-like pharmacology occur exclusively in ON type bipolar cells in fish retinas. Conversely in salamander, OFF bipolar cells utilize only AMPA receptors (96). This may also be the case in zebrafish retina where dissociated cells fail to respond to the kainate agonist SYM 2081 (86) and electroretinographic OFF responses (d-waves) are blocked by the AMPA antagonist GYKI 52466 (97). One might expect also that even within the broad classes of AMPA and kainate receptors, subforms may have evolved to fit particular visual niches. In salamander retina indeed, there are separate classes of AMPA receptors postsynaptic to rods and to cones (96, 98).

3 Bipolar-cell axons: ON and OFF lamination in the inner plexiform layer

In work performed at the National Institutes of Health in the mid 1970s (99, 100), it was noted that the ON or OFF property of cat retinal ganglion cells was related to the level of stratification of dendrites within the retinal inner plexiform layer. This led to a general scheme for ON and OFF layering illustrated in figure 14. The dendrites of OFF-center ganglion cells always arborize distal to the dendrites of ON-center ganglion cells. The zone of OFF-center dendritic arborization is called sublaminaa, while the zone of ON-center dendritic arborization is called sublaminab (Fig. 14). Within each sublamina ganglion cells make selective contacts with ON- or OFF-type bipolar cells. The pattern of ON and OFF layering of bipolar cell synaptic terminals and ganglion cell dendrites has proved to be a consistent pattern among all vertebrate retinas examined (101, 102). ON and OFF layering is particularly pronounced in retinas where ganglion cell types are predominantly monostratified. However, in more anatomically complex retinas, (i.e., turtle) with multistratified and/or diffusely stratified ganglion cell types, the ON vs. OFF layering pattern applies to monostratified cells only. The physiology of cells with processes ramifying throughout the IPL is more difficult to predict based on morphology alone (103).

Figure 14. Layering of ON and OFF bipolar cell axons in the cat inner plexiform layer (IPL). OFF ganglion cell (GC and GC) dendrites and OFF cone bipolar cell axons (OFF cb) co-stratify in sublamina a of the IPL. ON bipolar axons (ON cb) and ON ganglion cell dendrites co-stratify in sublamina b of the IPL. These are the parallel ON and OFF cone pathways that originate with bipolar-cell dendritic contacts with cones. The illustration is modified from Nelson et al, 1978 (100).

Stratification of cone bipolar cell axon terminals

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Bipolar Cell Pathways in the Vertebrate Retina by Ralph ...

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Cuddy, S., Letcher, R., Chiew, F.H.S., Nancarrow, B.E. and Jakeman, A.J. A Role for Streamflow Forecasting in Managing Risk Associated with Drought and Other Water Crises, Drought and Water Crises: Science, Technology, and Management Issues, ed Donald A. Wilhite, United States, Taylor & Francis CRC Press, pp 346-364 (2005)

Georgiou, S., Bateman, I.J. and Langford, I.H. Cost-benefit analysis of improved bathing water quality in the United Kingdom as a result of a revision of the European Bathing Water Directive, Cost Benefit Analysis and Water Resources Management, ed Brouwer, R. and Pearce, D.W., United Kingdom, Edward Elgar, 1: pp 270-289 (2005)

Hertzler, G.L. Prospects for Insuring Against Drought in Australia, From Disaster Response to Risk Management, ed Botterill, L.C., Wilhite, D.A., Netherlands, Springer, pp 127-138 (2005)

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Jakeman, A., Roganasoonthon, S., Letcher, R. and Scott, A. Improving integrated assessment approaches, Integrating knowledge for river basin management, ed Jakeman, A.J., Letcher, R.A., Rojanasoonthon, S., Cuddy, S. and Scott, A., Canberra, Australian Centre for International Agricultural Research, pp 203-219 (2005)

Letcher, R., Jakeman, A. and Ekasingh, B. Principles of integrated assessment, Integrating knowledge for river basin management, ed Jakeman, A.J., Letcher, R.A., Rojanasoonthon, S., Cuddy, S. and Scott, A., Canberra, Australian Centre for International Agricultural Research, pp 55-66 (2005)

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Soto, G.M.O. and Bateman, I.J. Cost-benefit analysis of urban water supply in Mexico City, Cost Benefit Analysis and Water Resources Management, ed Brouwer, R. and Pearce, D.W., United Kingdom, Edward Elgar, 1: pp 361-380 (2005)

Abadi Ghadim, A.K., Pannell, D.J. and Burton, M.P. Risk, uncertainty and learning in adoption of a crop innovation, Agricultural Economics, 33:1, pp 1-9 (2005)

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Chambers, R.G. and Quiggin, J. Linear-risk-tolerant, invariant risk preferences, Economics Letters, 86:3, pp 303-309 (2005)

Doole, G.J. Optimal management of the New Zealand longfin eel (Anguilla dieffenbachii), Australian Journal of Agricultural and Resource Economics, 49:4, pp 395-411 (2005)

Flugge, F.A. and Schilizzi, S.G.M. Greenhouse gas abatement policies and the value of carbon sinks: Do grazing and cropping systems have different destinies?, Ecological Economics, 55:4, pp 584-598 (2005)

Fraser, I. and Fraser, R. Targeting Monitoring Resources to Enhance the Effectiveness of the CAP, EuroChoices, 4:3, pp 22-27 (2005)

Georgiou, S. and Bateman, I.J. Revision of the EU Bathing Water Directive: economic costs and benefits, Marine Pollution Bulletin, 50:4, pp 430-438 (2005)

Gilmour, J.K., Letcher, R.A. and Jakeman, A.J. Analysis of an integrated model for assessing land and water policy options, Mathematics and Computers in Simulation, 69:1-2, pp 57-77 (2005)

Hart, R. and Latacz-Lohmann, U. Combating moral hazard in agri-environmental schemes: a multiple-agent approach, European Review of Agricultural Economics, 32:1, pp 75-91 (2005)

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John, M.B., Pannell, D.J. and Kingwell, R.S. Climate change and the economics of farm management in the face of land degradation: Dryland salinity in Western Australia, Canadian Journal of Agricultural Economics, 53:4, pp 443-459 (2005)

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Kingwell, R.S. Future Broadacre Farming Systems - a personal view, Connections, 1:Autumn 2005 (2005)

Lefroy, E.C., Flugge, F.A., Avery, A. and Hume, I. Potential of current perennial plant-based farming systems to deliver salinity management outcomes and improve prospects for native biodiversity: a review, Australian Journal of Experimental Agriculture, 45:11, pp 1357-1367 (2005)

Llewellyn, R.S., Pannell, D.J., Lindner, R.K. and Powles, S.B. Targeting key perceptions when planning and evaluating extension, Australian Journal of Experimental Agriculture, 45:12, pp 1627-1633 (2005)

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White, B. and Dawson, P.J. Measuring Price Risk on UK Arable Farms, Journal of Agricultural Economics, 56:2, pp 239-252 (2005)

Drewry, J.J., Newham, L.T.H., Greene, R.S.B., Jakeman, A.J. and Croke, B.F.W. An Approach to Assess and Manage Nutrient Loads in Two Coastal Catchments of the Eurobodalla Region, NSW, Australia, MODSIM05, Melbourne, Modelling and Simulation Society of Australia and New Zealand, 1: pp 2658-2664 (2005)

Hailu, A. and Schilizzi, S.G.M. Learning in a "Basket of Crabs": An Agent-Based Computational Model of Repeated Conservation Auctions, Nonlinear Dynamics and Heterogeneous Interacting Agents, Germany, Springer-Verlag, 8th: pp 27-39 (2005)

Ticehurst, J.L., Rissik, D., Letcher, R.A., Newham, L.H.T. and Jakeman, A.J. Development of Decision Support Tools to Assess the Sustainability of Coastal Lakes, MODSIM05, Melbourne, Modelling and Simulation Society of Australia and New Zealand, 1: pp 2414-2420 (2005)

Lindner, R.K. Impacts of Mud Crab Hatchery Technology in Vietnam, :1, pp 1-68, Canberra (2005)

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Bates, K.A., Harvey, A.R., Carruthers, M. and Martins, R.N. Androgens, andropause and neurodegeneration: exploring the link between steroidogenesis, androgens and Alzheimer's disease, Cellular and Molecular Life Sciences, 62: pp 281-292 (2005)

Camelo, S., Kezic, J. and McMenamin, P.G. Anterior chamber associated immune deviation: a review of the anatomical evidence for the afferent arm of this unusual experimental model of ocular immune responses, Clinical and Experimental Ophthalmology, 33: pp 426-432 (2005)

Charles, A.K., Hisheh, S., Liu, D., Rao, R.M., Waddell, B.J., Dickinson, J.E., Rao, A.J. and Dharmarajan, A.M. The expression of apoptosis related genes in the first trimester human placenta using a short term in vitro model, Apoptosis, 10:1, pp 135-140 (2005)

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Chisholm, J.S., Quinlivan, J.A., Petersen, R.W. and Coall, D. Early stress predicts age at Menarche and first birth, adult attachment and expected lifespan, Human Nature, 16:3, pp 233-265 (2005)

Dixon, K.J., Hilber, W., Speare, S., Willson, M.L., Bower, A.J. and Sherrard, R.M. Post-lesion transcommissural olivocerebellar reinnervation improves motor function following unilateral pedunculotomy in the neonatal rat, Experimental Neurology, 196: pp 254-265 (2005)

Eastwood, P.R., Platt, P.R., Shepherd, K., Maddison, K. and Hillman, D.R. Collapsibility of the upper airway at different concentrations of propofol anesthesia, Anesthesiology, 103:3, pp 470-477 (2005)

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Grounds, M. The Wonder of Stem Cells and their Clinical Applications, Australian Biochemist, 36:1, p 3 (2005)

Grounds, M.D., Davies, M., Torrisi, J., Shavlakadze, T., White, J. and Hodgetts, S. Silencing TNF alpha activity by using Remicade or Enbrel blocks inflammation in whole muscle grafts: an in vivo bioassay to assess the efficacy of anti-cytokine drugs in mice, Cell and Tissue Research, 320: pp 509-515 (2005)

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Co-Directors

Lance A. Liotta, MD, PhD Co-Director

Emanuel Petricoin III, PhD Co-Director

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Jianghong Deng, MS Biostatistician Email: jdeng@gmu.edu

Jianghong specializes in medical diagnostic tests, sample size calculation, survival analysis, predictive model development and high-dimensional data analysis technology. A user of SAS, R, and JMP, Jianghong is a member of the American Statistical Association and the American Association for Cancer Research.

Virginia Espina, PhD, MT(ASCP) Research Assistant Professor Email: vespina@gmu.edu

Dr. Virginia Espina is the former Manager of the Laser Capture Microdissection Core facility at the National Institutes of Health/National Cancer Institute, within the Laboratory of Pathology and the NCI-FDA Clinical Proteomics Program. Dr. Espina's career began as a Medical Technologist in clinical laboratories. She has extensive clinical laboratory experience, including clinical chemistry and Blood Bank. Her thorough knowledge of clinical quality control and quality assurance issues and regulations compliment her clinical research initiatives, which include phosphoprotein stability, effects of therapy on protein cell signaling pathways, and live cell/tissue microdissection. She currently has multiple roles in the Center for Applied Proteomics and Molecular Medicine, including CAP/CLIA laboratory director, research laboratory manager, instructor, and researcher. In varying degrees, she has been involved in a number of functional proteomics-based research projects and clinical trials at George Mason University and the National Institutes of Health/National Cancer Institute. The studies performed by Dr. Espina have involved a wide spectrum of proteomic approaches, including classical western blotting, laser capture microdissection and reverse phase protein microarrays, that yielded elucidation of phosphorylation specific kinase events in the tumor-host microenvironment of multiple myeloma, breast, lung and ovarian cancer. Dr. Espinas responsibilities include lab management for the CAP/CLIA compliant clinical trial laboratory, co-PI on a Breast DCIS chemoprevention clinical trial, as well as translational research involving nanoparticle applications for harvesting biomarkers, identification of breast cancer progenitor cells in pre-invasive lesions, and elucidation of cell signaling cascades in cancer and infectious disease. Dr. Espina is the lead scientist developing phosphoprotein preservatives as an alternative to formalin fixation.

Isela Gallagher, MS Research Specialist Email:rgallag3@gmu.edu

Iselas research incorporates laser capture microdissection, reverse phase protein microarrays, western blotting, and immunohistochemistry to investigate unique signaling pathway profiles in cancer tissue that can be utilized for diagnosis, prognosis, targeted therapeutics and individualized therapy.

Alessandra Luchini, PhD Assistant Professor Email: aluchini@gmu.edu

Claudius Mueller, PhD Research Assistant Professor Email: cmuelle1@gmu.edu Claudius' research focuses on protein pathway activation mapping in brain cancer (glioblastoma) as well as the development and optimization of new tissue stabilizing chemistries and fixatives that preserve the phosphorylation state of signaling proteins, while maintaining full diagnostic immunohistochemical and histomorphologic detail of cells and tissues.

Mariaelena Pierobon, MD Research Assistant Professor Email:mpierobo@gmu.edu

Alex Reeder, BS , MT(ASCP) Medical Technologist Email:kreeder@gmu.edu Alex is involved in research that focuses on translational breast cancer clinical trials. She uses laser capture microdissection, reverse phase protein microarrays and cell culture as primary technologies in her work. Alex analyzes protein signaling pathways in tissue to provide physicians with data to rationally select FDA-approved pharmaceutical treatments for breast cancer patients.

Sally Rucker, BS, MT(ASCP) Medical Technologist Email: srucker@gmu.edu Sally is involved in research that uses hydrogel microparticles to sequester and concentrate low abundance proteins, such as biomarkers or antigens, in complex biofluid samples. Her current focus is on early Lyme disease detection using these microparticles to concentrate Lyme antigens in urine, which can then be detected using an ELISA procedure. Sally also ensures the laboratory is CAP/CLIA compliant for upcoming clinical trials. This involves meeting all CAP/CLIA regulations and participating in proficiency testing surveys to monitor the labs performance on established tests.

Paul Russo, PhD Research Assistant Professor Email: prusso@gmu.edu Pauls research focuses on using multiple reaction monitoring mass spectrometry (MRM-MS) to quantitate and validate potential biomarkers for diseases including cancer, heart disease, and schizophrenia. After potential biomarkers are discovered by other mass spectrometry methods, Paul uses MRM-MS to validate and quantify data using larger sample sets. Paul is also developing a method using MRM-MS to quantitate human growth hormone (hGH) in human blood and urine to identify athletes who have doped.

Amy VanMeter Adams, MS Research Specialist Email:avanmete@gmu.edu Amys research focuses on using laser capture microdissection, western blotting and reverse phase protein microarray technology to investigate the phosphorylation events in signaling pathways for the discovery of new rational drug targets and mapping protein pathways which can be applied to disease diagnosis and prognosis Amy also directs The Aspiring Scientists Summer Internship Program that engages high school and undergraduate students in cutting edge scientific research related to Proteomics, Genomics, Neuroscience, Biochemistry, Chemistry, Biodefense, Nanotechnology, Bioinformatics, Computer Science, Physics and Environmental Science.

Julia Wulfkuhle, PhD Research Professor Email: jwulfkuh@gmu.edu Dr. Wulfkuhle has more than 10 years of experience in human tissue processing and preparation for Laser Capture Microdissection and in the field of functional signal pathway profiling of human cells and tissues using Reverse Phase Protein Microarray (RPMA) technology. She has contributed to methods development for sample preparation, printing, staining, image capture and analysis and has also been involved in the establishment of a set of reference standards and calibrators for RPMAs that will be used in the transition of this technology into a calibrated assay that can be used for standardization and quantification of staining intensities across arrays and between experiments. Dr. Wulfkuhles research interests include proteomic profiling of solid tumor tissues, including breast, prostate, lung and brain, for designing personalized therapeutic strategies, and identification of signaling mechanisms underlying resistance to targeted therapeutics.

Weidong Zhou, PhD Research Assistant Professor Email: wzhou@gmu.edu Weidong analyzes serum, tissue and cell lines using liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) for biomarker discovery relevant to cancer, Alzheimers disease, infectious disease, schizophrenia, and atrial fibrillation.

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Roles of Amacrine Cells by Helga Kolb Webvision

Helga Kolb

1. General characteristics.

Amacrine cells of the vertebrate retina are interneurons that interact at the second synaptic level of the vertically direct pathways consisting of the photoreceptor-bipolar-ganglion cell chain. They are synaptically active in the inner plexiform layer (IPL) and serve to integrate, modulate and interpose a temporal domain to the visual message presented to the ganglion cell. Amacrine cells are so named because they are nerve cells thought to lack an axon (Cajal, 1892). Today we know that certain large field amacrine cells of the vertebrate retina can have long axon-like processes which probably function as true axons in the sense that they are output fibers of the cell (see later section on dopaminergic amacrine cells). However these amacrine axons remain within the retina and do not leave the retina in the optic nerve as do the ganglion cell axons. Figure 1 shows one of the earliest depictions of the retinal cell types including amacrine cells drawn by Ramon y Cajal (circa 1890). These retinal cell types were visualized using the anatomical silver impregnation method devised by the Italian anatomist Camillo Golgi in the nineteenth century (Fig. 2).

Fig. 1. Drawing of the retina made by Cajal

Since the time of Cajal we have known that amacrine cells come in all shapes, sizes and stratification patterns. Since those days many more morphological subtypes have and continue to be described from further Golgi studies, intracellular recordings and immunocytochemical staining. Thus, we presently have a classification of amacrine cells consisting of about 40 different morphological subtypes.

Fig. 2. Picture of Camillo Golgi

It is useful and most easily understandable to group the amacrine cell types into the general descriptors of narrow-field (30-150 um), small-field (150-300 um), medium-field (300-500 um) and wide-field (>500 um) based on a measurement of their dendritic field diameters (Kolb et al., 1981). Then the next most important criterion of classification involves knowing the cells stratification. It is generally agreed now that the IPL can be subdivided into five equi-thickness strata or sublayers (Cajal, 1892) into which amacrine, bipolar and ganglion cell processes can be assigned. All of these cell types are now classified primarily on the stratum or strata of the IPL in which their dendrites or axons are located. This is because, as mentioned in previous chapters, the IPL of vertebrate retinas can be divided up into areas of neuropil where specific cells are put into synaptic contacts and form circuits only with cells earmarked for a particular functional role.

Many varieties of amacrine cell are monostratified, restricted to a single stratum, while others are bi- or tri-stratified. When amacrine or ganglion cell processes pass through all the strata of the IPL from distal to proximal or vice versa, they are called diffuse cells. Superimposed upon Cajals five strata subdivision of the IPL, is a sublaminar division of the IPL. The first two strata, 1-2, are known as sublamina a of the IPL while strata 3-5 are known as sublamina b by this scheme (Famiglietti and Kolb, 1976). It will be remembered from previous chapters that sublamina a contains bipolar axons and ganglion cell connections that lead to OFF-center ganglion cell physiology, while sublamina b contains bipolar to ganglion cell connections resulting in ON-center ganglion cell physiology (Nelson et al., 1978).

Figure 3 shows drawings of some small field amacrine cells of the monkey retina as seen in vertical sections (Polyak, 1941). Small-field cells like these can be well visualized in section because their dendritic trees are contained within the depth of the section. However, large field cells are not so well described in section where their dendrites get cut off.

Fig. 3. Amacrine cells of the monkey retina. Adapted from Polyak, 1941.

It was only when wholemount preparations, from Golgi staining (Stell and Witkovsky, 1972; Boycott and Kolb, 1973) or immunocytochemical staining (Karten and Brecha, 1980) were attempted that we could classify such cells. Then the full extent of their dendritic trees which can be up to one millimeter in spread could be visualized (Fig. 4) and a whole new understanding of amacrine cells became available.

Fig.4. Amacrine cells as seen in wholemountcat retina

A new technique of intracellular staining by a photochemical method has been developed in Richard Maslands group, as an alternative to the unreliable Golgi technique (MacNeil and Masland, 1998). Amacrine cells of the rabbit retina are labelled with the nuclear stain DAPI and then selected single nuclei are irradiated by a narrow beam of light to drive DAPI to the oxidation of non-fluorescent dihydrorhodamine 123 to the fluorescent rhodamine 123. The complete cell body and the dendritic tree is thus revealed under viewing in the fluorescence or confocal microscopes. By this method, 30 or so different varieties of amacrine cell can be photographed and drawn in full detail in the rabbit retina. 22 varieties of amacrine cell have been seen in Golgi preparations in cat and primate retinas so either some have been missed that were seen in rabbit, or else they are not as well deveoped in these less complex mammalian retinas. In any event the narrow field and medium field types revealed by MacNeil and Maslands work (1998) are shown in Figures 4a and b below. A further 5 different wide field monostratified types were also encountered in rabbit retina by this method (not illustrated). They correspond closely to the wide field types seen in monkey, cat and human (Fig. 4, above) (Mariani, 1990; Kolb et al., 1981, Kolb et al. 1992).

2. Amacrine cell circuitry as revealed by electron microscopy.

Kidd (1962) and later Dowling and Boycott (1966) were the first to identify the three types of profile that contribute to the IPL by electron microscopy. The electron micrograph (Fig. 5) below shows the cytological criteria on which we now recognize bipolar, amacrine and ganglion cell profiles in the neuropil. Thus bipolar cell axonal endings are recognized by being filled with synaptic vesicles and having a ribbon-shaped density (Fig. 5, red spots) pointing to two postsynaptic profiles (amacrine and ganglion). Amacrine profiles are also filled with synaptic vesicles but make synapses characterized by membrane densities at which the vesicles are particularly clustered (Fig. 5, yellow spots). Ganglion cell profiles are recognized as being only postsynaptic to either bipolar axons or amacrine processes, containing no vesicles but instead a content of neurotubules, ribosomes and glycogen granules.

Fig. 5. Electron micrograph of several profiles in the IPL

Amacrine cell synapses are frequently seen to be reciprocal to bipolar ribbon input, i.e. the amacrine returns a synapse in the vicinity of the ribbon input synapse (arrowheads). Most amacrine cells are inhibitory neurons in the vertebrate retina, containing the common inhibitory neurotransmitters GABA or glycine. GABAergic amacrine cells, in particular, typically make reciprocal synapses with bipolar cells. A17 is the most well studied of the GABAergic reciprocal amacrine cells in the retina and we shall return to this cell later.

We have learned much concerning the synaptic relationships of certain narrow-field amacrine cells as well as bipolar and small ganglion cell types such as midget ganglion cells of the primate retina, from reconstructions of serial-section electron micrographs. The circuitry of the AII amacrine cell in the cat retina was first appreciated by this means (Kolb and Famiglietti, 1974; Famiglietti and Kolb, 1975; Kolb, 1979). However, with the advent of intracellular dye injection of electron-dense materials (horseradish peroxidase, HRP, or the photoreduction of Lucifer yellow) after physiological recordings or the development of electron dense immunostains for electron microscopy, neurocircuitry was made easier for us. We could look at amacrine cells and their synaptic inputs by study of fewer sections and it was not as critical to photograph every single section in a series. The amacrine cell of interest would always be clearly marked black, and easily found in the synaptic neuropil. It is from this technique that we have learned most about amacrine cells and their circuitry in the mammalian retina. The remainder of this chapter will describe the morphology, circuitry and intracellular responses of the amacrine cells that are most completely understood at present.

3. A2: narrow-field, cone pathway amacrine cell.

A2 is a narrow-field amacrine with a 20-60 um wide dendritic tree composed of multibranched, beaded and appendage-bearing dendrites mostly confined to stratum 2 of the IPL (Fig.6).

Fig. 6. Golgi drawings of A2 amacrine cellsin cat and human retinas

Intracellular recordings from A2 cells (formerly called A4) indicate that these cells give true slow potential hyperpolarizing response to light (OFF-center) at all positions of the slit in their receptive fields and they have no sign of an inhibitory surround (Fig. 7) (Kolb and Nelson, 1984).

A2 cells receive bipolar input from OFF-center types of cone bipolar cell of sublamina a and make reciprocal synapses to these bipolar axons (Fig. 7). A2 amacrine cells then synapse upon OFF-center ganglion cell dendrites of sublamina a. The A2 cell makes an inhibitory synapses upon these ganglion cells, because it is thought to be a glycinergic cell type (Wassle et al., 2009 ).

A possible role for A2 amacrines is in disinhibition of the ganglion cells center responses. Alternatively, A2 cells, despite being small-field types, might have a role in the generation of antagonistic surrounds of ganglion cells (Kolb and Nelson, 1993). A2 cells receive a great many amacrine inputs to their dendritic trees which could be from wider field cells than they are are themselves so giving them a much larger receptive field size than their actual dendritic tree size would indicate.

Fig. 7. Summary diagram of A2 amacrine cells wiring pattern and physiological responses to light

A3, knotty Type 2 amacrine cells.

A small-field amacrine cell that branches in S2 and S3 (i.e. across the sublamina a/b border) is seen in cat and human retina with Golgi staining (Kolb et al., 1981; Kolb et al., 1992) (Fig. 7a). The same amacrine has been called a knotty Type2 amacrine cell in Golgi studies (Mariani, 1990) and immunostaining in the macaque retina (Klump et al., 2009). The A3 cell is clearly immunostained with parvalbumin (Fig. 7b) and has the typical A3 morphology and small field multibranched dendrites with large varicosities (Fig. 7a, b) (Klump et al., 2009). The varicose dendrites branch broadly through strata S2 and S3, so they are in a position to interact with both flat midget cone bipolars or other narrow field cone bipolars of the OFF sublamina a, and with cone bipolar cells of stratum 3 in the ON sublamina b.

Fig. 7a. A3 or knotty type 2 amacrines are seen in whole mount Golgi staining (left) and their physiological response to light is an ON center response (right) (adapted from Klump et al., 2009).

Fig. 7b. Parvalbumin-mmunostained A3 or knotty type2 cells and their neurotransmitter and connectivity. a) An isolated PARV+ amacrine is a small field amacrine cell that branches primarily in S2 and S3 of the IPL (arrow heads show the IPL borders to the inner nuclear layer (INL) and to the ganglion cell layer, GCL). b-d) Shows that the A3 cell colocalizes PARV+ (b) (green) and the glycine transporter Glyt-1 (c) (red) (d) colocalization in yellow). e) The A3 amacrine (green) makes synaptic contact (f) with recoverin-IR flat midget bipolar cells (red) in S2 of the IPL.

A3 or the PARV+ amacrine can be seen to be glycinergic when double immunostained for either glycine (Wassle et al., 2009) or the glycine transporter Glyt-1 (Fig. 7b, the PARV+, A3 colocalizes parvalbumin and Glyt-1, a-d). This small field A3 amacrine has been intracellulaly recorded from by Klump and co-authors (2009) and proves to give an ON response to light stimulation (Fig. 7a, right traces). The PARV+ amacrine is situated amongst the axon terminals of flat (OFF) midget bipolar cells in S2 of the IPL and appears to be either pre or postsynaptic where apposing immunostained profiles occur (Fig. 7b, e and f). The A3 PARV+ cell is also know to be presynaptic to OFF parasol ganglion cells in sublamina a and interact with AII amacrine lobular appendages and starburst amacrine cells of sublamina a (Bordt et al., 2006). A3 cells are also extensively coupled into a network of the same cell type by gap junctions (Klump et al., 2009). The latter authors suggest that A3, knotty Type2 amacrines are driven by ON pathway cone bipolars and inhibit OFF pathways and through synapses upon AII amacrine cells inhibit the transmission of rod signals to these same OFF pathways.

4. AII: a bistratified rod amacrine cell.

Fig. 8. AII amacrine cells intracellularly stained after physiological recording by different methods

Above are shown four examples of the best studied amacrine of all in the vertebrate retina: the AII rod amacrine of the mammalian retina. These cells have been recorded from by microelectrodes and dyes have been iontophoresed into the cell after the intracellular recordings (Nelson, 1982). The AII cell, was first described from Golgi staining and electron microscopic examination (Famiglietti and Kolb, 1975; Kolb and Famiglietti, 1974).

AII is a narrow field amacrine (dendritic tree diameter typically 30-70 um) with a bistratified morphology: the mitral shaped cell body gives off a single, stout apical dendrite and a cluster of lobular appendages (round blobs just below the cell body, Fig. 9) arise from the main dendrite in sublamina a of the IPL (Fig 9). The finer arboreal dendrites (Vaney et al., 1991) penetrate down into sublamina b to end close to the ganglion cell layer (Fig. 9). AII amacrine cells are glycine-immunoreactive (Pourcho and Goebel, 1985; Crooks and Kolb, 1992) and contain the calcium binding proteins parvalbumin, calbindin and calretinin (Wssle et al., 1995). Figure 10 shows a Golgi stained AII amacrine cell in cat and human retinas as seen in a surface view of a wholemount.

Fig. 9. Parvalbumin staining of AII amacrine cells in hamster retina.

Fig. 10 Golgi stained AII amacrine cells seen in wholemount.

In cat and rabbit retinas where AIIs have been recorded from, the AII cell is a rod-dominated depolarizing (ON-center) cell (Bloomfield, 1992; Dacheux and Raviola, 1986; Nelson, 1982). Thus, in the center of its receptive field the cell gives a transient depolarizing response with a pronounced sustained plateau (ON-center) and a long drawn out hyperpolarization after light off (Fig. 11). By 140 um to either side of the center, the response to a light flash is now an inverted response indicating a hyperpolarizing surround (OFF-surround) (Fig. 11) (Nelson, 1982).

Fig. 11. Schematic diagram of the morphology, physiology and wiring pattern of the AII amacrine cell

Electron microscopy has shown that the AII, is primarily postsynaptic to rod bipolar axon terminals in lower sublamina b of the IPL (30% of its input, Strettoi et al., 1992) (Fig. 12, left). Some OFF cone bipolar input is directed at the AIIs lobular appendages in sublamina a (Fig. 13). AIIs major output is upon ganglion cells that have dendrites only in sublamina a. AII cell lobular appendages synapse upon OFF-center ganglion cells (Fig. 12, right) and to OFF-center cone bipolar cell axons (possibly cb1 and cb2 types) in sublamina a (Fig. 13) (Kolb, 1979).

Fig. 12. Electron micrographs of AII amacrine synapses

The AII also passes rod-driven information through the ON-center cone bipolar axons in sublamina b to ON-center ganglion cells by means of gap junctions (Fig. 12, center panel) (Kolb and Famiglietti, 1974; Famiglietti and Kolb, 1975; Kolb, 1979). Several, if not all, cone bipolar axons of sublamina b have gap junctions with AII cell dendrites. A new finding is that even the blue-cone bipolar receives rod signals through this gap junction pathway (Field et al., 2009). AII cells also join with other AII cells by gap junctions in sublamina b of the IPL (Fig. 13, lowest gj) (Famiglietti and Kolb, 1975; Nelson, 1982; Vaney, 1994a). Summary Figure 13 shows the major input and output circuitry of the AII amacrine cell.

Thus, AII cells are almost totally rod-driven by the rod bipolar input in sublamina b of the IPL. However some cone pathway bipolar cell input occurs to their ON-center responses. This could come from from excitatory input from ON-center cone bipolars at the gap junctions (gap junction transmitting both ways), from direct OFF center cone bipolar axon synapses in sublmina a, unlikely, or from other intermediary ON amacrine cells of the cone system (such as A8 and A13, knotty parvalbumin-IR amacrines; Klump et al., 2009).

Fig. 13. Schematic drawing of the wiring pattern of the AII amacrine cell

Click here to see an animation of the wiring pattern of the AII amacrine cells (Quicktime movie)

Several amacrine synapses are seen throughout the AII cells dendritic tree by electron microscopy (Kolb, 1979; Strettoi et al., 1992, Fig. 13, red as). Most of these are unidentified as yet. However, a dopaminergic amacrine cell provides a considerable number of synapses to the AII cell, either directly upon its cell body or upon its lobular appendages (Voigt and Wssle, 1987; Kolb et al, 1991) (see later section on dopamine amacrine cells, A18). Dopamine cells are thought to have a function in the inner retina to uncouple AII amacrine cells from both their contacts with the depolarizing cone bipolar and the AII amacrine coupled network (Daw et al., 1990; Vaney, 1994a). As much as 51% of the input to AII amacrine cells is from various other amacrine cells though, and most of these inputs occur in the central part of the cells dendritic tree in strata 3-4 (Strettoi et al., 1992).

Thus the AII amacrine cells are the major carriers of rod signals to the ganglion cells in the retina. As such they play a role in speeding up the slow potential rod messages for presentation to ganglion cells (Nelson, 1982; Smith, 1994). Their distribution in the retina suggests that they tile the complete retina (Vaney, 1990). AII amacrine cells peak in density at 1.5 mm from the foveal center in monkey and at the area centralis in cat (Vaney, 1984). In addition, because of their high density across all parts of the retina and their synaptic involvement with millions of rod bipolar cells, they may contribute in a major way to the pattern ERG (Zrenner, 1990).

5. A8: a bistratified cone amacrine cell.

A8 is a bistratified, narrow-field amacrine cell which is easy to confuse with AII in wholemount, stained retina (Fig. 14). It actually looks like an upside-down AII cell. A8 has short, wispy processes coming from the apical dendrite to ramify in sublamina a of the IPL whereas heavy beaded dendrites penetrate down to sublamina b, to run in strata 4 and 5. This cell type may correspond to the DAPI-3 of the rabbit retina, described by Vaney (1990) and Bloomfield (1992). It is a glycinergic amacrine cell (Pourcho and Goebel, 1985; Crooks and Kolb,1992; Wassle et al., 2009, Neumann and Haverkamp, 2012).Very recently the A8 amacrine cell population has been demonstrated to immunostain for the protein synaptotagmin-2 (Syt2) in macaque monkey retina (Neumann and Haverkamp, 2012). Syt2 cells peak at a density of 1400/mm2 at 1-2 mm and subside to 22/mm2 at 9-10 mm of eccentricity (Neumann and Haverkamp, 2012).

Fig. 14. Golgi and HRP appearance of A8 amacrine cells

The A8 cell has been intracellularly recorded and studied by electron microscopy after iontophoresis of horseradish peroxidase. In Fig. 15 we can see the synapses of this cell type.

Fig.15. Synapses in the IPL of a HR-peroxidase injected A8 cell

The A8 amacrine cell is involved in the cone pathways of the cat retina, rather than the rod pathways, that the AII is committed to. Thus, in sublamina a, excitatory cone driven signals come from cone bipolar cells like cb2 which we know are OFF center in physiology (Fig. 15a), and in sublamina b from cb6, another OFF-center bipolar cell (Fig. 15d) (Nelson and Kolb, 1983). Altogether cone bipolar synapses account for 42% of the input to A8 cells. Lesser rod bipolar input (20%) also occurs to the lower dendrites in sublamina b of the IPL. Like AII amacrine cells, A8 cells also engages in gap junctions with a cone bipolar type of sublamina b, but the bipolar is a different type, possibly cb6, and in addition to the gap junction makes the common ribbon synapse to A8 dendrites (Figs. 15c and d). A8s major output is to OFF-center beta ganglion cell dendrites in sublamina a of the IPL (Fig. 15b). We have not seen A8 synapses to OFF-center alpha cells in the cat retina (Kolb and Nelson, 1996). The input and output synapses for A8 amacrine cells are seen in the summary diagram of Figure 16 and the animation below.

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Roles of Amacrine Cells by Helga Kolb Webvision

Gonadotropin-releasing hormone (GnRF), molluscan …

Recently gonadotropin-releasing hormone (GnRF)-like and molluscan cardioexcitatory peptide (FMRFamide)-like compounds have been colocalized immunocytochemically to the terminal nerve, a presumed olfactoretinal efferent system in goldfish. In the present study these and related neuropeptides were shown to affect ganglion cell activity, recorded extracellularly, when applied to the isolated superfused goldfish retina. GnRF was usually excitatory. Salmon GnRF (sGnRF) was 10-30x more potent than chicken or mammalian GnRF. FMRFamide and enkephalin also were often excitatory but caused more varied responses than sGnRF. Met5-enkephalin-Arg6-Phe7-NH2 (YGGFMRFamide), which contains both enkephalin and FMRFamide sequences, tended to act like both of these peptides but with mainly enkephalin-like properties. Neuropeptide Y and the C-terminal hexapeptide of pancreatic polypeptides, whose C-terminus (-Arg-Tyr-NH2) is closely related to that of FMRFamide (-Arg-Phe-NH2), gave no consistent responses. Threshold doses were equivalent to: 0.1 microM for sGnRF; 0.5 microM for YGGFMRFamide; 1.5 microM for FMRFamide and enkephalin. Rapid, complete and irreversible desensitization was induced by single, 10-20x threshold doses of sGnRF; but desensitization was infrequent and limited with the other peptides. In general, all peptides tested affected the spatially and chromatically antagonistic receptive field components similarly, but selective actions were seen in a few cases with FMRFamide and with the opioid antagonist, naloxone. Responses, especially to sGnRF and FMRFamide, tended to be most frequently obtained and pronounced in winter and spring, suggesting a correlation with seasonally regulated sexual and reproductive activity. Our observations provide further evidence for transmitter-like roles of neuropeptides related to sGnRF and FMRFamide in the teleostean terminal nerve. The actions of agonists and antagonists, singly and in combination, imply strongly that there are distinctive postsynaptic receptors and/or neural pathways for GnRF-, FMRFamide- and enkephalin-like peptides in the goldfish retina.

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Gonadotropin-releasing hormone (GnRF), molluscan ...

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