Bedford Research Foundation 2013 Newsletter

Read about all of the progress and the research that has occurred at the Foundation over the course of the past year! Dr. Kiessling outlines her vision for the upcoming year as well. Thank you for your support.


“Off-the-shelf” Engineered Stem Cells: Are They Therapeutically Valuable?

The astounding 2013 report by an Oregon research team of the successful creation of stem cells from a somatic cell nucleus transferred into an unfertilized human egg was met with surprising calm by the lay press and the bioethics community. This is in sharp contrast to the outcry a decade ago when similar experiments were denounced as “human cloning” and the U.S. congress rumbled with attempts to outlaw all such research with human eggs. Public concern was further fueled by an extraordinary scientific fraud in 2005 by a South Korean research team that falsely claimed to have created such stem cells.

The 2013 calm is a clear, positive sign that the newness — and the shock — of the promise of stem cell regenerative medicine has worn off. Thousands of young scientists have been trained since the 1999 cover of Science announced stem cells as the “breakthrough of the year.”

So where are the stem cell therapies? Where are the cures for diabetes, spinal cord injuries/diseases, stroke, HIV/AIDS, Parkinson’s disease, heart and kidney failure? Are they coming?

The answer is yes. But painfully slowly for the patients and families in need. Why?

Because new therapies involve both new scientific discoveries and additional tests for medical safety. Demonstrating that stem cells can turn into heart muscle or nerve cells in a petri dish is exciting, but very far from therapeutic use.

One big stumbling block is the source of the stem cells to be used for therapies.Must they be patient-specific? Or could a bank of fully characterized, “off-the-shelf”stem cells be created? Stem cells that could be administered immediately in the emergency room when the heart attack,stroke or spinal cord injury occurs?Perhaps while patient-specific stem cells were being created

According to estimates, only a few hundred stem cell lines could tissue match more than 95% of the world’s population.

This is an exciting prospect and an achievable goal. The stem cells could even be genetically engineered if needed to treat specific conditions, such as HIV/AIDS.

Bedford Research Foundation scientists are pursuing a promising example of engineering stem cells — to have a resistance to HIV infection. The work follows a proof-of-principle report by a German medical team in 2009. Because HIV infects the immune system, it is theoretically treatable by bone marrow stem cell transplant. But past attempts have shown transplanted bone marrow becomes HIV infected, making it an unsuitable treatment approach for HIV disease. This changed when the bone marrow transplant in Germany resulted in an apparent cure of the patient’s HIV disease — because the transplanted bone marrow stem cells were naturally deficient in CCR5, an receptor on the surface of cells important for HIV infection.

Without the receptor, cells are resistant to HIV infection.

Now the task at hand is to create stem cells missing CCR5 that are tissue matched to the HIV infected person. Deleting CCR5 in patient-specific (e.g. nuclear transplant, induced pluripotency, testis or parthenote) stem cells might work. “Off-the-shelf”, engineered stem cells might also work if they tissue match the patient. Our 2013 Activated Egg Symposium brings together pioneers in genetic engineering (Mario Cappeccchi and Rudolf Jaenisch) with stem cell specialists (Treena Arinzeh, Gordon Carmichael, Kim Tremblay, Jose Cibelli, David DiGiusto) and a member of the Oregon SCNT team, David Battaglia, to present their work and perspectives in research areas important to move the work forward as fast as safely possible to patient therapies. Bedford Research scientists are positioned to move faster than some traditional academic laboratories because we are not dependent upon federal funds. The parthenote research, highly promising for modifying stem cell genes, cannot be funded by the NIH because of long-time federal funding restrictions. Much of our laboratory overhead is funded through fee for service laboratory testing, allowing research donations to go directly to research. We are accountable to individual donors to return the maximum value for every dollar given to the research. Private donations — of all sizes — are essential to achieving the research speed needed by patients.

Thank you for your support.

With gratitude,

Ann A Kiessling, PhD

BSCRF Scientists Discover Developmental Differences Between Mouse Embryos and Parthenotes

Figure 2: Histogram of timing of cell cleavages following fertilization (top) or parthenogenetic activation (bottom). Wavy background line is temperature (right axis).

The current goal of BSCRF research is to optimize the efficiency of deriving pluripotent stem cells from testis and unfertilized human eggs (parthenotes) for patient specific and perhaps stem cell bank use.

In 2009, Bedford Research scientists discovered that circadian rhythm genes are“on” in early human embryos, suggesting circadian signals may be important to stem cell derivation and stability. If true, new methods of culturing stem cells in laboratories that mimic circadian signals need to be developed.

In the body, the rhythm of circadian genesis supported by several types of signals,including light/dark cycles, hormone pulses, body temperature variations, and eating. The signals regulate the pattern of circadian genes turning “on” and “off” in 24 hour cycles. In contrast, to date, stem cells have been cultured in constant temperature in the dark, their only potential circadian signal being renewal of their culture medium.

To begin to understand the importance of circadian temperature oscillations to stem cell derivation and expansion, BSCRF scientists have taken advantage of their newly developed “circadian incubator time lapse video microscope” to chronicle the first five days of development of mouse embryos and parthenotes, which are being used as models because cell division is easy to see in a group of mouse embryos/parthenotes. The goal is to discover if temperature oscillations play an important role in stem cell derivation or differentiation into useful cell types, such as neurons or bone marrow stem cells.The work is ongoing.

As shown in Figure 2, results to date indicate the first cleavage of a mouse egg to two-cells takes place at approximately the same time after fertilization or parthenogenic activation, the second cleavage to 3 cells and 4 cells is markedly delayed in the parthenotes, the intervals to the third cleavages (5 to 8 cells) are approximately the same, but development to blastocyst is again delayed in the parthenotes. This indicates the parthenotes need additional developmental support at the 2-cell stage and at the 8- to 16-cell stage. Discovering the needed support, and its relationship to circadian signals, may markedly improve testis and parthenote stem cell derivation, and speed up the project to derive genetically modified parthenote stem cells.

Progress In Testis Stem Cells

Thanks to generous donations, BSCRF scientists are in Phase III of the human testis stem cell project.

That the adult human testis contains pluripotent stem cells, in addition to sperm stem cells, was a surprising report by two research teams a few years ago. Thanks to private donations, Bedford Research scientists are determining the efficiency with which this naturally occurring source of pluripotent cells can be isolated and expanded into therapeutically useful,patient-specific stem cells. They have adopted Good Laboratory Practices for the testis stem cell derivation to shorten the time to FDA approval of derived lines.

Phase III is a collaboration with Dr. Martin Dym, Georgetown University, who has generously provided cryopreserved biopsies of the testis tissues their lab used.One of the challenges with testis stem  is distinguishing pluripotent stem cells (about 500 per gram of tissue) from the sperm stem cells (about 5 million per gram of tissue) that actively divide to produce many millions of sperm daily –the proverbial needle in a haystack. If the cell dynamics are similar to bone marrow,the pluripotent stem cell is quiescent until activated, in contrast to the sperm stem cell that is actively renewing. Current experiments in the Bedford lab are taking advantage of this difference to help isolate the stem cells

At The ISSCR

Dr. Kiessling (left) answers questions during a poster session at the meeting.

In June, 2013, BSCRF presented a poster and hosted a booth at the 11th Annual International Society for Stem Cell Research meeting. The poster titled,“Onset of Period 2 Oscillation Coincides with Differentiation of Mouse Embryonic Stem Cells” was selected from a record number of abstracts submitted. It reported the conclusion that the important circadian gene, Period 2, is turned on in stem cells,but begins to oscillate throughout the colony when the stem cells begin to differentiate. Although the importance of circadian rhythms to organ function is growing in recognition, the Foundation’s report was one of only two on circadian rhythms at the ISSCR.

New Staff

Alexis Agnew joins the team as our SPAR coordinator,bringing over ten years of medical experience in both private practice and the US Air Force. SPAR is instrumental in helping couples living with HIV disease safely parent.

 

Valia Dinopoulou, a one-year fellow, hails from the laboratory of Dr. Dimitrius Loutradis, Professor and Chairman of Obstetrics,Gynecology and Reproductive Biology, University of Athens, Greece. Valia will work on the project to genetically engineer parthenote stem cells.

Who is Bedford Research Foundation?

Philanthropy Is The Key To Continued Progress

The average cost of each experiment is $90,000. Because much of our overhead is covered by fee-for-service laboratory tests, 92% of every dollar donated goes directly toward these experiments. This innovative funding model allows Bedford Research scientists greater flexibility to move quickly in promising new research directions.

Continued progress requires meeting our annual funding goal of $450,000 in 2019.

Donate Today!

Human Somatic Cell Nuclear Transfer For Patient Specific Stem Cells: Will It Work?

What is Somatic Cell Nuclear Transfer (SCNT)?

SCNT is a phrase coined by scientists to describe the process of injecting the nucleus (which contains the chromosomes) from another cell in the body into a human egg. Last week a team of Oregon scientists reported creating four unique stem cells by this process (Cell, June, 2013 (pdf)). This work is a follow-up to studies originally reported by Bedford Research Foundation scientists, Jose Cibelli and Ann Kiessling, in 2001 (Somatic Cell Nuclear Transfer in Humans: Pronuclear and Early Embryonic Development. J of Regenerative Medicine (pdf)).

Why are the new stem cells important?

Stem cell-based treatments, termed regenerative medicine, are being developed to replace defective tissues and organs such as heart and kidney failure, spinal cord injury and disease, diabetes, AIDS, Parkinson’s and Alzheimer’s diseases, and degenerative joints. The source of the stem cells is key. If they can be harvested from the patient, there will be no problems with tissue rejection, such as can happen with kidney or heart or bone marrow transplants from donors. SCNT provides a powerful method to create stem cells with the patient’s own chromosomes, thus a perfect tissue match. SCNT had been accomplished in many species, but not human.

human egg blue dnaThe human egg is a huge cell, that is released from the ovary surrounded by cells that support it. The blue areas shown above are the DNA, the genetic information contained within each cell. The cluster of blue within the egg is the egg’s chromosomes, half of which will be expelled when the sperm enters, so the developing embryo will have genetic information from both the mother and the father.For parthenogenesis, the egg chromosomes alone guide development, for SCNT, the chromosomes are usually removed with a tiny pipette so the only genetic information remaining is from the transferred nucleus.

Background to SCNT

SCNT was first performed several decades ago to test whether or not every cell in the body contains all the genetic information of the individual. For example, does a liver cell contain all the genetic information to form every other type of cell, but “non-liver” genes are silenced? Or does a liver cell lose other genes and only retain “liver” genes?

Dr. John Gordon received the Nobel Prize in 2012 for demonstrating in 1958 that tadpole cell nuclei contained all the chromosomes necessary to form new frogs following transfer into frog eggs whose own chromosomes had been removed. The new frogs were genetically identical to the tadpole. Frogs were the first cloned animals.

For nearly three decades, it was believed that although successful with amphibia, mammals could not be cloned by transferring a nucleus into an egg, although other types of studies had confirmed that all cells contain all the genetic information needed to form a new being.

In 1997, to the surprise of the scientific community, Dolly the sheep was cloned by SCNT into a sheep egg, thus proving that like frogs, mammals could also be cloned from a single cell (Ian Wilmut at the Activated Egg Symposium (video)). Since then, many species have been similarly cloned, including mice, rats, rabbits, dogs, goats and cattle.

What is the magic contained within an egg?

Perhaps partly because of its enormous size, an egg has a unique capacity to remodel the structure of chromosomes, including its own and those of sperm. The remodeling allows expression of all the genetic information needed for stem cell pluripotency. Without being fertilized by sperm, eggs can be activated to generate stem cells, parthenote stem cells (1 min video about Parthenotes), using their own chromosomes. Parthenote stem cells have all the pluripotency characteristics of stem cells derived from human embryos (1 min video about hES). These studies suggested that SCNT would be highly successful in human eggs.

Why no human SCNT cells before now?

The inability to derive a line of stem cells from SCNT into human eggs has been a mystery, thought to be related to the status of the egg itself.

Thirteen years ago, Bedford Research scientists (JRM, 2001 (pdf)) reported side by side experiments activating human eggs parthenogenetically and by SCNT. Although 12 out of 22 parthenote eggs did divide and progress to the blastocyst stage, only 3 out of 19 SCNT eggs divided once or twice, and none progressed to the blastocyst stage (schematic). These results led to the current ongoing work by Bedford Research scientists to fully characterize gene expression in normal 8-Cell human embryos to begin to understand the problems with human parthenotes and SCNT eggs (JARG 2010JARG 2009).

eight cell human embryo
8-cell human embryo

A few years later, a large South Korean scientific team, well experienced in SCNT and animal cloning, reported the successful generation of several stem cell lines from SCNT into human eggs. The reports were quickly dispelled by other South Korean scientists as being totally fraudulent. This was a huge blow to the integrity of the stem cell scientific community.

Nonetheless, the lesson learned from the South Korean reports is that they had access to approximately 2,000 human eggs and had been unsuccessful in SCNT. This revealed loud and clear that there was a fundamental difference between human eggs and those of other mammals.

Two years ago, a New York scientific team headed up by Dieter Egli (AES 2011Time 2011) reported deriving SCNT stem cells from human eggs whose chromosomes had not been removed (Nature, Vol 478). There was something helpful about leaving the human egg chromosomes in the egg during the activation process. This is regarded as an important breakthrough even though the resulting stem cells contain twice as many chromosomes as normal stem cells.

And now comes the Oregon scientific team reporting the successful derivation of SCNT stem cell lines by utilizing advances in egg culture, activation, and chromosome removal. Nonetheless, that unknown egg-specific factors play a role, however, was shown by marked differences in SCNT success rates.

Unfortunately, there are irregularities in the manuscript reported in Cell (Science Magazine, May 23, 2013), thus once again casting a shadow over the work. Other scientific teams are currently investigating the cell lines to determine the accuracy of the report.

Are SCNT eggs actually embryos?

Accuracy of language for new technologies involving human eggs will provide the balanced framework necessary for everyone to evaluate the value — and the threat — of SCNT technology (CT law review). If “embryo” is reserved for the unique union of egg and sperm, and if other activities of human eggs have more accurate terms, such as parthenote for eggs activated with their own chromosomes, and SCNT-egg (or “ovasome”) for eggs activated following SCNT, there will be far less confusion, especially by the non-scientific community.

Whether or not SCNT-eggs should be assigned the same status as embryos since there is the potential — however small — that such an entity could develop further if transferred into a uterus (“human cloning”) is a separate consideration from whether or not they should be termed “embryos.” New technologies need new terms.

 

 

Bedford Research Foundation 2012 Newsletter

Read about all of the progress and the research that has occurred at the Foundation over the course of the past year! Dr. Kiessling outlines her vision for the upcoming year as well. Thank you for your support.


Four Years of the Spinal Cord Workshop

At the Frontier of Stem Cell Research and Spinal Cord Injury

The 2009 Workshop in partnership with University of Georgia and the Shepherd Center

Since 2008, the Spinal Cord Workshop has brought together international leaders in surgery and basic science to debate and develop a list of the challenges to cures for spinal cord injury. The goal of the workshop is to develop a “white paper,” listing the obstacles.

The workshop has brought to light such problems as how researchers use animal models to test theories, how to measure outcomes from studies (i.e. what defines success?), and the distribution of funds.

Additionally, the researchers have pointed out a significant lack of corporate involvement because of the limited market size, considering that spinal cord injury, while devastating, effects only 11,000 new patients every year. Therefore, most corporations are unwilling to invest in SCI treatments,even if discoveries could cascade to help a host of other diseases in the future.

Participants have expressed the importance of intimate workshops like this one, to allow for a space to share not only scientific discoveries, but also failures. Much of scientific progress is failure and in the current “success story only”environment, scientists and physicians don’t have the chance to share the side of the research that leads to many important discoveries: what doesn’t work in the lab.

The reports from these clinician scientist are easily accessible at the Foundation’s website. For more information about this year’s spinal cord workshop, www.SpinalCordWorkshop.org to read an interview with Dr. Kiessling about what she learned this year, and what you can do(in addition to donating) to help.

The 2013 Activated Egg Symposium

Mario Capecchi, PhD

Nov 8, 2013: Dr. Mario Capecchi will keynote the tenth annual AES. Dr. Capecchi is a Distinguished Professor of Human Genetics & Biology at the University of Utah School of Medicine,an Investigator with the Howard Hughes Medical Institute, and a Nobel Laureate for Physiology & Medicine, 2007.

Dr. Capecchi is best known for his pioneering work on the development of “gene targeting” in mouse embryonic stem (ES) cells. This technology allows scientists to create mice with mutations in any desired gene. The power of this technology is that the investigator chooses both which gene to mutate and how to mutate it. This allows scientists to evaluate in detail the function of any gene of the mouse.

Testis Stem Cell Project

Thanks to private donations, BSCRF scientists are in Phase 3 of the testis stem cell project.

Testis tissue may be a readily available source of patient-specific stem cells for men, and may take less time to develop and characterize than the iPS cells Professor Yamanaka received the Nobel Prize for this year. Bedford Research scientists are taking advantage of their more than two decades of experience with testis tissues to collaborate with Dr. Martin Dym, Georgetown University, who reported deriving pluripotent stem cells from testis biopsies in 2009.

Dr. Dym has generously shared some of the cryopreserved tissues used in his original report so Bedford Research scientists can improve the stem cell derivation process.

Phase 4 will use fresh biopsies from male volunteers for this study to establish the success rate. Phase 4 will begin in 2013, if funds are available.

First Circadian Incubator Videomicroscope

The PER2Luc mouse has circadian genes coupled with firefly “Luciferase” genes. When the circadian genes turn “on” they glow, dimly, like a firefly

Three years ago Bedford Research Foundation scientists discovered that circadian rhythm genes may be important for stem cells. If true, new ways of culturing them need to be developed.

The question is: what circadian signals to test? A signal common to all mammals is a daily fluctuation in body temperature.

BRF scientists are taking advantage of a mouse strain that has been engineered to glow when the circadian rhythm genes are active. BRF scientists derived two embryonic stem cell lines from this mouse strain, and are conducting studies to determine if circadian temperature oscillations play a role in stem cell growth and tissue development.

A characteristic of embryonic stem cells is the ability to aggregate together and form embryonic muscle cells of the heart. Work is in progress to see if this process involves expression of circadian rhythm genes.

2012 New Jersey Stem Cell Symposium Keynote

Dr. Kiessling was the Keynote Speaker at the Symposium on September 19, 2012, “Totipotency, Pluripotency and Growth Factors.” The sixth annual symposium attracted over 240 scientists.

SPAR Presented at HIV Forum in Washington, D.C.

A roundtable, “Safe Conception and Reproductive Options for HIV-Infected Individuals” organized by the Forum for Collaborative HIV Research, UC Berkeley School of Public Health, featured a presentation about SPAR by Dr. Kiessling. The Foundation’s specialized HIV-infertility program now has over 170 healthy babies, www.SemenTesting.org.

Prostate Cancer Research Project Update

Clinton McCabe

Dr. Joseph Ciccone

Dr. Robert Eyre

Dr. Robert Eyre

Dr. Robert Eyre, and his colleague, Dr. Joseph Ciccone, collaborate with Bedford Research scientists to develop improved early detection tests for prostate cancer.

Following up work Dr. Eyre reported at the New England chapter of the American Urologic Association, the team is recruiting men needing prostate biopsy for cancer detection to also provide specimens for the new Bedford Research screening test.

The test under development will screen semen specimens, half of which are fluids and cells from the prostate gland, for the presence of genes that are over-expressed and under-expressed specifically in prostate cancer.

Recent concerns about the lack of specificity of the PSA test, currently the only available screening test for prostate cancer besides prostate biopsy, have increased the importance of this study. The goal is to provide physicians and their patients with a more accurate screening test for cancer, that also distinguishes aggressive cancers from slow-growing tumors. The research is being coordinated at BSCRF by Clinton McCabe.

A New Branch Of Medicine

Letter from the Director About Research at the Foundation

19 identical albino frogs created by nuclear transplantation into unfertilized eggs.

Fifty years ago, John B. Gurdon discovered frogs could develop from the genetic material of a single adult cell transplanted into a frog egg, the first cloned animal. The experiment was done not to clone frogs, but to ask a question: do adult cells contain all the genetic information needed for embryonic development.

 

John Gurdon’s experiment answered the question,genetic information is not lost in adult tissues, it is selectively turned off or on.

This heralded a new era of cell discovery that took 50 years for the Nobel Committee to recognize and award Professor Gurdon the Nobel Prize in Physiology and Medicine this year. For the next 34 years, however, it was believed that only frogs, not mammals, could be cloned from adult cells, a viewpoint astoundingly reversed by the successful cloning of Dolly the sheep in 1996.

Embryonic stem cells were derived from mouse embryos in the early 1980’s and from human embryos in 1998. The remarkable capacity of embryonic stem cells to multiply in culture, and become every cell type in the body, heralded a new era of regenerative medicine.

We are now nearly a decade and a half into that era, with astounding scientific progress being made all over the world, but little in the way of therapies. Why?

What are the obstacles to translating laboratory discoveries into off-the-shelf therapies? Is it the way the experiments are designed in the laboratories that does not translate into the safety studies required by the Food and Drug Administration? Is it unnecessary bureaucracy? Is it lack of coordination among the groups needed to go from bench to bedside?

Dr. Yamanaka’s discovery of induced pluripotent stem cells may eliminate the need for embryos.

One known barrier to stem cell therapy is the need for transplanted cells to not be rejected as “foreign.” Cell rejection would be avoided if stem cells could be derived from the patient’s own cells, rather than from a stem cell bank. Toward this end, Shinya Yamanaka discovered in 2007 a new method to re-program adult cells into pluripotent cells, thus replacing eggs. The discovery so captured the attention of the global scientific community that laboratories all over the world quickly confirmed Yamanaka’s findings, thus lifting stem cell research out of the controversy associated with human embryos. Dr. Yamanaka shared the Nobel prize this year with Professor Gurdon.

 

The prospect of regenerating damaged tissues and organs is arguably the most exciting development of modern medicine. Spinal cord injury seems especially suited for regenerative medicine because the injury is usually a well-defined lesion in an otherwise healthy adult. This year’s 2012 Spinal Cord Workshop is a frank discussion among leaders in the field to pinpoint, and hence correct, the principal barriers to cure SCI. Once identified, those barriers could also apply to other diseases, such as heart disease, diabetes, Parkinson’s Disease,stroke, multiple sclerosis, AIDS, and cancer.

We are witnessing the development of a new branch of medicine, with all its growing pains.

Dr. Steven L. Stice, Dr. Hans Keirstead, Dr. Ann A. Kiessling and Dr. Wise Young at the first Spinal Cord Workshop in 2008

At this time, there is no consensus on the best source of stem cells, the best way to program pluripotent stem cells into the tissue needed, and how best to guard against unwanted growth of stem cells that could lead to cancer. Bedford Research Foundation scientists remain focused on how to improve the efficiency of deriving patient-specific stem cells from naturally pluripotent sources, including unfertilized eggs and testis, and whether or not the discovery by BRF scientists a few years ago that circadian rhythms may play a role is true

 

My frustration about how much more BSCRF could accomplish each day with more people, more money, is balanced by pride in our ability to do more with less, and by gratitude to the supporters and committee members who believe in our mission. Our administrative costs are low,our ratio of new information/research dollar spent is high, our goals are lofty.

With gratitude for your support,

Ann A Kiessling, PhD
Director, Bedford Research Foundation

Who is Bedford Research Foundation?

Philanthropy Is The Key To Continued Progress

The average cost of each experiment is $90,000. Because much of our overhead is covered by fee-for-service laboratory tests, 92% of every dollar donated goes directly toward these experiments. This innovative funding model allows Bedford Research scientists greater flexibility to move quickly in promising new research directions.

Continued progress requires meeting our annual funding goal of $450,000 in 2019.

Donate Today!

Dr. Ann Kiessling Devotes Full Time to Bedford Stem Cell Research Foundation

The Bedford Stem Cell Research Foundation has announced that Dr. Ann Kiessling, its award-winning founder and executive director, is stepping down from the Harvard Medical School faculty after 27 years to devote her full attention to the stem cell research and other initiatives of the Foundation.

“My nearly three decades at Harvard have been wonderful, highly productive years for the two areas of NIH-funded research in my laboratory: reproductive biology of eggs and early embryos, and semen transmission of HIV. Being surrounded by highly talented HMS faculty, both clinical and basic science, stimulated our thinking and shortened the timeline to research answers,” said Dr. Kiessling, a nationally recognized pioneer in stem cell and HIV research.

Read More

To PSA or Not to PSA: That is the Question

The current raucous debate over the commonly used PSA blood test to screen for prostate cancer, the third leading cause of cancer deaths in men in the U.S.(a), stems from the U.S. Preventive Services Task Force’s recommendation to discontinue PSA screening(b). The debate is pitting physician against physician, cancer advocacy groups against health care insurance companies, and leaving men with enormous questions about what to do about their lifetime risk of developing prostate cancer.

The Task Force’s recommendation is based on its review of medical literature that concluded that PSA screening leads to more unnecessary treatment complications than are justified by lives saved because of:

  1. the questionable accuracy of the PSA test to detect cancer,
  2. medical complications caused by unnecessary follow-up procedures because the PSA test has false positives, and
  3. increasing pressures to slow the rate of increase of medical care

However, the well meaning conclusion by the U.S. Task Force to discontinue PSA screening is not likely to be followed by all physicians because of the negative consequences of missing a cancer if PSA screening is not performed.

A large European study has clearly demonstrated, however, that PSA screening reduces deaths from prostate cancer by 20%(c,d). Therefore, until there are better options, PSA screening is unlikely to be abandoned, but the results need to be put in the context of individual prostate cancer risk and other medical indicators in order to minimize unnecessary invasive procedures. New guidelines for follow-up diagnostics and treatment need to be developed, and there is an urgent need for better prostate cancer screening tests, like those being developed for semen specimens by Bedford Research Foundation scientists.

BACKGROUND

PSA is an acronym for “prostate specific antigen,” a protein made specifically by the prostate gland. The biological role of the prostate is to contribute fluids and proteins to semen at ejaculation. The other glands that contribute fluids and proteins to semen are the seminal vesicles. The prostate and seminal vesicles contract at ejaculation; the seminal vesicles contribute proteins that are extremely large, making semen thick, thus concentrating the sperm in the vagina, close to the cervix, the opening to the uterus. PSA is a specific type of protein, an enzyme, that is capable of breaking up the large seminal vesicle proteins, making them shorter and less viscous, allowing the sperm to swim free of the ejaculate, through the cervix into the uterus and fallopian tubes in search of an egg.

Another biological role for the proteins and fluids contributed by the prostate to ejaculated semen is to block negative responses to sperm by cells of the immune system in the vagina to protect the female reproductive organs from bacterial infection. Laboratory studies by Bedford Research scientists have shown that even very small amounts of semen added to cultures of immune cells causes them to die within 24 hours(e). It seems possible that this suppression of immune response to protect sperm has the unwanted side effect of making the prostate gland itself “immune suppressed” and thus less capable of protecting itself from infections and cancer. Some men suffer from low grade infections of the prostate for years, a condition known as “chronic prostatitis.” Other men may also have chronic prostatitis, but without symptoms. Some studies indicate that chronic, low-grade infections can eventually lead to cancer.

Like most cancers, prostate cancer has several forms, many of which are so slow-growing that they are not life threatening — not unlike a wart. Others are highly threatening because they grow very fast and invade surrounding tissues. The various types of prostate cancers are best distinguished by examination of small pieces of the prostate (biopsies) by a trained pathologist. Even then, it is sometimes difficult to distinguish fast growing from slow growing cancers, grouped under the general term “neoplasias” (“new growth”).

Because like other cancers, early prostate cancer can have no symptoms and not be detected during a physical exam of the prostate, the development of the PSA screening test in the late 1980’s was greeted with enthusiasm as an additional tool to protect men from death by prostate cancer. Because it was a blood test, it was initially thought to predict cancer spread, beyond the prostate gland itself, into surrounding tissues, including the spine and the blood stream. It is now known, however, that cancerous prostate cells actually produce less PSA than normal prostate cells, so blood levels of PSA do not necessarily mirror tumor size or spread. A further complication of PSA screening is that many fast growing prostate cancers never lead to elevations in PSA levels. Moreover, chronic, low-grade infections, and the gradual increase in the size of the prostate gland that accompanies aging can also lead to elevated PSA in blood samples. The reason for this is unknown.

STUDIES CAUSING DEBATE

By the mid 1990’s many studies to refine the use of PSA blood tests to predict prostate cancer had appeared. Some suggested following changes in PSA levels over time, some suggested isolating different forms of PSA in blood, e.g. “bound” or “free.” But none of the refinements increased the specificity of the PSA blood test to distinguish prostate cancer from other diseases of the prostate, nor to always detect prostate cancer itself.

In March, 2009, the results of two large studies to determine the usefulness of testing blood samples for PSA were reported in the New England Journal of Medicine. The U.S. study(f) enrolled 76,693 men from 1993 to 2001: 38,343 to receive annual PSA screening and 38,350 to receive “usual care” to serve as the control group. Eighty six percent of the “annual PSA screening” group actually received annual screening for six years, and up to 52% of those in the “control group” also received annual PSA screening, markedly decreasing the power of the study to distinguish the long term effects of annual PSA screening after 7 to 10 years of follow-up. In contrast, the larger European study(c) enrolled 182,000 men in seven European countries (Netherlands, Belgium, Sweden, Finland, Italy, Spain and Switzerland) who were randomly assigned to receive PSA screening at an average of once every four years, or to receive no PSA screening. After an average of 9 years of follow-up, the death from prostate cancer in the screening group was 20% lower than in the control group. A more recent two-year follow-up to the original 9 years(d) confirmed that death from prostate cancer was 21% lower in the screening group at 11 years of follow up than in the control group.

Importantly, both the U. S and European study teams noted the high rate of complications and unnecessary surgeries resulting from both false-positive PSA screens, and highly invasive surgeries for slow-growing cancers that were in all likelihood not life threatening.

GOING FORWARD

That PSA screening prevents death from prostate cancer has been clearly demonstrated by the large European study. They are careful to note, however, that preventing death from prostate cancer did not influence “all cause mortality,” suggesting no over-all lengthening of life span.

One way to prevent the complications and unnecessary surgeries that result from PSA screening is to not do it anymore, as has been recommended by the U.S. Task Force. Another way to prevent such problems is to adjust the responses of physicians and patients to the results of PSA screening. The panic that sets in at the mere thought of a cancer diagnosis needs to be treated first, before further diagnostics are initiated. Patients need to be able to keep in perspective the difference between a diagnosis of prostate cancer and the risk of dying from prostate cancer. The table illustrates the difference in the rates of death of the top five(a) cancers in men:

Estimated New Cancer Cases and Deaths in U.S. Men for 2012, All Races

Primary Site Estimated New Cases in 2012 Estimated Deaths in 2012 Ratio of Deaths/New Cases
Prostate
241,740
28,170
0.12
Digestive System
(esophagus to rectum, liver and pancreas)
156,760
80,560
0.51
Respiratory System
130,270
91,110
0.70
Urinary System
(bladder and kidney)
97,610
19,670
0.20
Lymphoma and Leukemia
69,950
24,490
0.35

Cancer Facts & Figures, 2012, American Cancer Society; excludes basal and squamous cell skin

Having by far the lowest ratio of Deaths to New Cases emphasizes the slow growing nature of most prostate cancers. The aggressive U.S. campaigns to encourage people to get tested for cancer as a life-saving measure have been very successful, with many cancers detected at early enough stages for successful treatment. Bedford Research Foundation scientists are laying the groundwork for additional screening tools for early detection of prostate cancer in semen specimens.

But until new prostate cancer screening tools are developed and tested, it is time to launch a campaign about prostate cancer that emphasizes most are not life threatening, and overly-aggressive treatment of an elevated PSA screening test may cause life altering side effects far worse than living with the cancer itself.

  1. National Cancer Institute, National Institutes of Health, American Cancer Society Cancer Facts and Figures (pdf).
  2. Screening for prostate cancer. U.S. Preventive Services Task Force, 2008.
  3. Screening and prostate-cancer mortality in a randomized European Study. N Engl J Med 2009;360:1320-8.
  4. Prostate-Cancer Mortality at 11 Years of Follow-up. N Engl J Med 2012;366:981-990.
  5. Seminal Plasma Induces Programmed Cell Death in Cultured Peripheral Blood Mononuclear Cells. Aids Res and Human Retroviruses, 2002,18:797-803. .pdf attached
  6. Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med 2009; 360:1310-1319.

 

 

Over-Regulation of Parthenotes Stifles Valuable Scientific Research

Sean Kealy, UPenn Law RegBlog

A recent article in Scientific American questioned whether research on stem cell lines derived from unfertilized eggs was too tightly regulated by the federal government. Now that technology allows the creation of stem cells without fertilization, there is no question that federal laws and guidelines are overly restrictive, causing a detrimental effect on valuable scientific inquiry.

Since 1996, Congress has included the Dickey-Wicker Amendment in the annual federal budget. This amendment was a conservative reaction to what some considered to be scientific research that showed little respect toward life.

Read more: Over-Regulation of Parthenotes Stifles Valuable Scientific Research

Why I Support Stem Cell Research

Victoria Staebler

 

My support for stem cell research has its foundation in my deep-seeded belief in reproductive rights for women. Since I came of age in the 1970’s, women’s reproductive rights and freedom have been continually eroded by federal and state legislation. That has been coupled with diminished government support and funding – ranging from access to abortion services to stem cell research. Because of that, I have volunteered time and donated money to help preserve these rights.

But last summer, my support for stem cell research became personal. During a mugging on the Cape, my stepson was shot by the assailant, resulting in a severed spinal cord at T-5. He’s now a parapalegic. The stem cell research that BRF is doing is laying the foundation for regenerative cell therapy that could potentially cure not only spinal cord injury victims like him, but an incredible range of diseases, from Parkinson’s to bone marrow cancer.

In our current divisive political environment, I don’t believe we will see any support from either the federal government or the National Institute of Health for years to come. So it’s up to us as individuals to move this initiative forward. I’ll bet there’s a personal connection for many of you as well. Please donate, volunteer and spread the word.

Victoria StaeblerVictoria Staebler is a member of the Bedford Stem Cell Research Foundation’s Board of Trustees. She is a Financial Advisor at Merrill Lynch and serves on the board of the Boston Club.

 

 

Testis Stem Cell Project Update

Thanks to private donations, BSCRF scientists have launched the testis stem cell project.

Phase 1 is the isolation of a new line of testis stem cells from the Per2Luc mouse to study the role of circadian genes in testis stem cells. Phase 2 is to improve the efficiency of deriving testis stem cells from cryopreserved (frozen to stay alive) Per2Luc testis tissues. Phases 1 and 2 are underway.

Phase 3, starting in early 2012, will be to collaborate with Dr. Martin Dym, Georgetown University, in deriving human testis stem cells from cryopreserved biopsies archived in his laboratory. We will compare the efficiency of testis stem cell derivation using our newly developed circadian culture conditions with the efficiency previously reported by Dr. Dym.

Phase 4 will derive patient-specific stem cells from the male volunteers for our study

Progress in Circadian Rhythms And Stem Cells

Circadian Rhythms in Early Embryos

BSCRF’s new mouse embryonic stem cells, PL034 (learn about the first incubator videomicroscope).

BSCRF scientists have derived two unique lines of stem cells that may lead to a breakthrough in the efficiency of stem cell derivation and expansion.

BSCRF scientists are following up their discovery that the genes that regulate the rhythms of daily life, circadian rhythm genes, may play important roles in stem cell derivation and stability in culture. Circadian rhythm genes regulate cells in the body by turning “on” and “off” over a 24-hour cycle in response to signals such as light/dark cycles, hormone pulses, and body temperature variations.

Currently, stem cells are cultured in constant temperature in the dark. If BSCRF’s research proves that circadian rhythm genes play important roles in stem cell division and stability, it could markedly improve the efficiency of stem cell derivation and expansion, urgently needed to produce major advances in stem cell therapy.

 Circadian Rhythm Genes: turn “on” and “off” in response to the rhythm of daily life.

To conduct this research, foundation scientists are using a genetic technology that links the circadian genes of a mouse with a gene from a firefly. When the circadian gene is “on”, the mouse cells glow like a firefly; when the circadian gene is “off”, the cells go dark. This mouse, “PER2Luc,” was derived by a circadian gene scientist several years ago and has been used by Dr. Fred Davis of Northeastern University, to study circadian gene expression in mouse tissues.

BSCRF scientists have derived two new lines of embryonic stem cells from PER2Luc embryos. Light emitted by the stem cells is detectable in Dr. Davis’s luminometer, but BSCRF scientists are developing microscope equipment to record light emitted by individual cells in order to compare standard stem cell culture conditions with new culture conditions that support circadian rhythm such as the temperature variations of a mouse. These new stem cells will also be useful to all scientists seeking to understand the relationship between circadian rhythm and cell functions