Countless sources are reporting on the “three parent embryo” created as a potential treatment for infertility.  What has not been reported is that ther is an almost 10 year history of unreagulated human experimentation in this arena which led to a rare federal ban on specific fertility treatments.  Is this hope, hype or dangerous human experimentation?  Read on to see!

Background- what are mitochondria?  Mitochondria are tiny primite organisms that millions of yers ago became incorporated into human cells.  They exisit in every cell but have their own unique genetic material. They function as the engines of the cell providing energy for metabolism.  I wrote an review of how they got there and what they do that you can read here.  In short mitochondria have their own DNA (similar to that of bacteria) and reproduce independently of the cell in which it is found.  We now have a symbiotic relationship with them.  

First - the details receontly reported by the BBC.  Diseases of the function of mitochondria exist.  “About one in every 6,500 people is affected by such conditions, which include fatal liver failure, stroke-like episodes, blindness, muscular dystrophy, diabetes and deafness.”  Details of their human experiment:  Scientists in the UK experimented on 10 embryos left over after IVF fertility treatments.  They microsurgically removed the nucleus, containing the embryo’s DNA  and implanted it into a donor egg whose DNA had also been removed. The donor egg while missing its DNA still contained its mitochondrial DNA.  They watched these embryos grow in the petri dish for 6 days. 

Therefore the resulting embryo will have the DNA of the donated nucleus but the mitochondrial DNA of the host cell- curing and potentially eradicating - the mitochondrial illness. 

This is not the first time this has been done.  The fertility treatment history of human experimentation on this:  While I was teaching at Yale Medical one of my partners and mentors in the fertility department (Dr David Keefe) was actively pursuing research on mitochondrial dysfunction as a cause of human infertility.  At that time a few fertility doctors in the US theorized that one cause of human reproductive aging was accumulated damage to the mitochondria in the egg. They thought the genes of the egg could be healthy but the rest of the egg that supports its become faulty.  They experimented with a technique called cytoplasmic transfer.  Using a microscopic needle tiny drops of fluid were sucked out of a donor’s egg and injected into that of an older infertile woman hoping to breath new energy and life into it.   Unfortunately most research groups found it did not seem to offer any benefit.

Reasons why it likely did not work:

1. using minute drops of fluid from a donor egg into a recipient is just not enough to correct the metabolic problem or defect
2. my collegues at Yale found that the mitochondria in the egg is often tightly joined to the nucleus so the cytoplasmic transfer did not move enough of them
3. a huge proportion of age related egg defects are related to nuclear not mitochondrial DNA defects.

The federal government banned this treatment in 2001.  Some feared that chromosomal abnormalities and birth defects could result if there were three people’s DNA in one embryo.  Federal officials decided that any method involving the transfer of genetic materials without the fusion of egg and sperm requires the oversight and involvement of the Food and Drug Administration.  The US legislation leading to the FDA taking jurisdiction over human eggs sperm and embryos is a whole other topic to be covered in later posts.   A brief overview of this from Rodger Gosden (who I know and respect as a leading reproductive biologist) is posted here from 1999 when this treatment was at its heyday with references justifying its use from mouse research.

The next brouha using the technique in humans in 2003:   Related research on nuclear transfer was again presented at the annual ASRM meeting in San Antonio in 2003.  I was in the audience for the talk and remember it well.  One of the researchers was an American out of NYU Dr Jaime Grifo who also used to be in my ex-department at Yale.  He is also a repected researcher who I know well.  Unable to perform the research in the US- the experiment was performed in China.  as reported here and here 

Researchers at Sun Yat-sen University in Guangzhou implanted three embryos in the womb of a 30-year-old infertile woman… A triplet pregnancy resulted, they announced at the annual meeting of the American Society for Reproduction Medicine in San Antonio, Texas this week. One of the foetuses was “reduced” to ensure the viability of the pregnancy, but the other two died anyway at 24 and 29 weeks.

With this technique, called nuclear transfer, the doctors fertilised an egg from their patient and an egg from a donor. Two embryos resulted. The nucleus of both women’s embryos was extracted, and the patient’s genetic material was inserted into the empty “eggshell” of the other embryo which, however, contained mitochondria with the other woman’s DNA. The procedure gives the infertile woman’s embryo the healthy mitochondria it needs to develop — but it also results in a child with genetic material from one father and two mothers.

Dr Grifo has maintained that he was an advisor and did not partake in the actual experiment.  NYU issued a statement that if the research was performed in China their IRB did not have oversight (different than my department where all work I did anywhere fell under the IRB as a faculty member).  I have never asked him his take on this but do respect him and strongly do not believe he is someone who would knowingly break the law or do what he felt was wrong.

Nonetheless- the ASRM responded with a moratorium on any future presentations on cloning (whether this was cloning is a whole other debate- many feel not). 

The technique is still undergoing related research:  I chair the video committe of the American Societry for Reproductive Medicine (ASRM) the largest international fertility research society.   Just this past year we accepted a video presentation on how to technically perform the procedure from a research team in Japan.  The paper- Embryonic Development Following the Nuclear Transfer of In Vitro Matured Metaphase-II Oocytes into Enucleated Freshly Ovulated Metaphase-II Oocytes by Tanaka and collegues investigated the possibility of repairing either mitochondrial diseases or female infertility due to ooplasmic deficiency and abnormalities. They demonstrated embryonic development following the nuclear transfer of in vitro matured metaphase-II oocytes into enucleated freshly ovulated metaphase-II oocytes and concluded it could be applied to the treatment of mitochondrial diseases or female infertility due to ooplasmic deficiency and abnormalities. 

More is certainly to come. 

Scientists in the UK have successfully tricked stem cells from a female to develop into sperm.  If these cells are functional then the possibility exists for an “all-female” baby to be made from the cells of a same sex female couple.  This is the next step forward from a group that earlier did the same thing with cells from a man.

This study was reported in the British Telegraph Newspaper.  They listed it as embryonic stem cells from a female human embryo - they are likely wrong - as I read the report it appears to be cells isolated from an adult female human bone marrow. 

This same group from Newcastle University led by Prof. Karim Nayernia reported last year that they had made a sperm from the bone marrow of an adult man.  I reported on this research in my previous post Babies Without Men and how it opened the possibility of making sperm from a female and creating a female-female baby.  The details of the original project, ethical and genetic risks  and  heated (and sometimes nasty) debate on lesbian-lesbian parenthood are here.

He now reports that he has repeated the experiment and made the sperm from the marrow cells of a female.  The work has not yet been published not subjected to peer review. 

I previously reported that I think there is a ticking genetic time bomb here due to imprinting errors.  The genes that come from your mother and father are in some cases marked as such genetically and one copy may be shut off.  In some cases only the gene from mom is active in others only the one from dad.  This new process may mess with this system - and imprinting errors are known to cause genetic diseases in some cases.  In fact, the telegraph reports of some “problems”

Prof Nayernia showed the potential of the method in 2006, when he used sperm derived from male embryonic stem cells to fertilise mice to produce seven pups, six of which lived to adulthood, though the survivors did suffer problems.

They also report it could be used to make eggs from a gay man’s cells “a gay man to donate skin cells that could be used to make eggs, which could then be fertilised by his partner’s sperm and placed into the uterus of a surrogate mother.”

While they also report he is seeking permission to create a baby in this way, the UK is very restrictive on new reproductive technologies.  They have a law- the 1990 Human Fertilisation and Embryology Act- that restricts what can and cannot be done. 

When does human life begin and what is a human?  Fertility specialists wrestle with this question every day as embryos are created, frozen, thawed, implanted, and discarded.  Occasionally an embryo is even “adopted”.  Today I received the draft results of a US government Health and Human Services Research Project that I participated in on the potential for embryo adoption in the US.

In 2002, the U.S. Congress authorized the Secretary of Health and Human Services to conduct a public awareness campaign to educate Americans about the existence of frozen embryos available for adoption.   Today I received the research report of the commission’s results:

Between April 4, 2005 and July 27, 2005, the Social Science Research Center (SSRC) at California State University Fullerton contacted 481 Assisted Reproductive Technology (ART) Centers in the United States, including yours, soliciting participation in a survey study. Attached to this message, please find a copy of the final report based on the 254 ART clinics that participated in this study.  This document is being distributed in response to interest in the results of the study expressed by many ART clinics.

The report begins 

Embryo adoption is a relatively new process in which individuals who have their own frozen embryos agree to release them to a recipient couple. The intent is to transfer into the womb of the recipient mother the donated embryos so that she and her partner may bear a child and  be that child’s parents. The number of embryos currently in storage in the Untied States was estimated at approximately 400,000. Of this number 88% are still being used by the creating families for their own family building efforts. Still, the remaining 12% or 48,000 embryos cannot be overlooked. Assuming an embryo transfer success rate of 30%, these 48,000 embryos could result in the birth of more than 14,000 children to infertile couples.

Under Public Law 107-116 (the Fiscal Year 2002 Department of Labor, Health and  Human Services, Education and Related Agencies Appropriations Act), the U.S. Congress authorized the Secretary of Health and Human Services to conduct a public awareness campaign to educate Americans about the existence of frozen embryos available for adoption.

There are 126,160 Human Embryos In Storage In the USA:  The  mean number of embryos stored across the centers is 1,208.89, and the median is 531. Overall, 126,160 embryos were being stored.

How Common is Embryo Adoption in US IVF/ART Programs:   43% of the programs indicate that their fertility center had a functioning embryo donation/adoption program during the previous year. 44% report that their fertility center currently had such a program.  Considering clinics with a current embryo donation/ adoption program and those reporting plans to implement such a program, almost 60% of the ART centers in the survey sample are likely to sponsor a program by this time.

How is Embryo Adoption Done in the US Now?:  75.1% of  fertility centers refer patients to outside sources for information regarding embryo donation/ adoption. Centers that do not currently have embryo donation/ adoption programs are more likely to refer their patients to outside sources for information on this topic than centers that do. Even among fertility clinics that do currently have embryo donation/adoption programs, however, the proportion who make outside referrals is still substantial (64.5%).  The largest proportion (59.7%) of clinic managers who refer patients to outside sources, refer their patients to the Snowflakes program. 7.9% refer their patients to embryoadoption.org; and 5.4% each to the National Embryo Adoption Center and to the Cooper Clinic. Less than 1% refer to “Embryos Alive.

Don’t Call it Adoption: Preferences for naming the transfer of embryos between couples were

1. Embryo Donation (65.6%)
2. Embryo Adoption (24.9%)
3. Some Other Term (9.5%)       obviously the term adoption is value laden to equate an embryo with a living child

Where Are The Embryos Stored?:  The majority of center staff report that their fertility centers store their patients’ frozen embryos at their clinic location, while nearly 10% report subcontracting for embryo storage.

Most Clinics Don’t Know How Many Embryos They Have!  Of the center staff indicating that their fertility center tracks the number of embryos it has stored, an astonishing majority (63.4%) indicate that they don’t know how many frozen embryos are currently stored, and another nine refused to answer this question.

When Do the Clinics Belive Human Life Begins?  “How do you characterize your fertility center’s general approach or philosophy with regard to the point at which embryos are thought of as human lives?” Ninety-six (37.8%) centers replied, “Don’t Know” in response to this question, and 37 (14.6%) refused to answer, illustrating the highly sensitive nature of this issue. Of those who did respond, the largest proportion (39.8%) say that “Embryos are considered human lives at conception,” followed by 33.9% that report, “Embryos are considered to be human lives after viability of pregnancy” and 15.3% that answered, “Embryos are considered human lives after implantation into the uterine lining”

Chipping Away at Roe v Wade:  Lost Embryo is Wrongful Death.  An Illinois appellate court ruled that a couple could sue their fertility center for wrongful death when the fertility center inadvertently discarded the couple’s frozen embryos. many clinics expressed concern or policy changes as a result.

The Relation To Stem Cells and Partial Birth Abortion:  The Stem cell connection is clear with so many groups arguing for the use of these embryos in storage to create stem cells.  The recent partial birth abortion ban announcement is another step to equate the fetus with human life and rights.  It will be interesting to follow how the classification and rights of these embryos evolves and see how that plays into the political debate on when life begins.  The Bush administration is very clear in its drive to push embryo adoption.

My Perspective as a Fertility Doctor:  My personal experience is that almost no patients ever request that their spare embryos be donated to other couples.  The vast majority simply prefer to leave them in frozen limbo in storage indefinitely - avoiding having to make a final decision of what to do with them.  As a result of the enormous expense and liability this poses to the clinics, private companies are forming to store the embryos off-site.  Many also choose to thaw them and discard them letting them die in the laboratory dish.  Occasionally a couple will choose to donate the embryo to research.  Why don’t more couples choose to donate to other couples?  I believe it’s a mixture of fear of the unknown (who the parents will be, would they ever run into their donated child?)  and lack of information regarding the process.  The problem will only grow as more embryos are frozen and success rates increase (limiting the need to use the frozen embryos). 

European Disasters From Limiting Embryo Freezing Legislation: 

• Italy passed the Medically Assisted Reproduction Law in March 2004, which prohibits the destruction of embryos created outside the body. This means that all embryos created during IVF (to a legal maximum of three) must be transferred to the woman’s womb- and within months infertile women were becomming pregnant with triplets despite the unwanted risks.
• In Spain, it is legal to put embryos in frozen storage, but it is illegal to destroy embryos or to donate them to research, despite the fact that 74 per cent of Spanish patients with spare embryos in storage would like to donate them to research. Because most couples would prefer not to donate their embryos to other patients, there are currently 50,000 embryos sitting unused in frozen storage in Spain
• The Embryo Protection Act of 1990 in Germany states that no more than three eggs can be collected from a patient for fertilization in vitro. After that, all embryos created must be transferred to the patient in order to avoid any embryo freezing or destruction. The result has been lower pregnancy rates and higher multiple pregnancy rate

NOTE TO READERS: this post is a copy of the full article and discussion which can be found here- please click for the many many comments

Scientists report today on the ability to create sperm from bone marrow cells.  Initially performed in men, the technique could potentially be performed in women and lead to a sperm cell made from a woman’s body.  You got it right- that cell could then fertilize an egg leading to the first female-female conception in human history.

As a fertility specialist I couldn’t resist this story and wanted to share the reality and the hype.  Prof. Karim Nayernia, Professor of Stem Cell Biology at the Instatute of Human Genetics at the Univeristy of Mewcastle on Tyne led the project reported in Biology of Reproduction.  A summary of the study was released in the Independent today.

The researchers said they had already produced early sperm cells from bone-marrow tissue taken from men. They believe the findings show that it may be possible to restore fertility to men who cannot naturally produce their own sperm.

But the results also raise the prospect of being able to take bone-marrow tissue from women and coaxing the stem cells within the female tissue to develop into sperm cells, said Professor Karim Nayernia of the University of Newcastle upon Tyne.

The report suggests that “Scientists are seeking ethical permission to produce synthetic sperm cells from a woman’s bone marrow tissue after showing that it possible to produce rudimentary sperm cells from male bone-marrow tissue.”

The Two Mommy- No Daddy Baby Making Research Plan:

“Theoretically is it possible,” Professor Nayernia said. “The problem is whether the sperm cells are functional or not. I don’t think there is an ethical barrier, so long as it’s safe. We are in the process of applying for ethical approval. We are preparing now to apply to use the existing bone marrow stem cell bank here in Newcastle. We need permission from the patient who supplied the bone marrow, the ethics committee and the hospital itself.”

If sperm cells can be developed from female bone-marrow tissue they will be matured in the laboratory and tested for their ability to penetrate the outer “shell” of a hamster’s egg - a standard fertility test for sperm.

“We want to test the functionality of any male and female sperm that is made by this way,” Professor Nayernia said. But he said there was no intention at this stage to produce female sperm that would be used to fertilise a human egg, a move that would require the approval of the Human Fertilisation and Embryology Authority.

This same group reported last year that they created artifical sperm from embryonic sperm cells in mice. 

(They) isolated stem cells from blastocysts, which are early-stage embryos only a few days old.  From these cells were extracted those that would go on to form sperm, known as spermatogonial stem cells (SSCs). The SSCs were then cultured in the laboratory, and when some developed into sperm, they were injected into female mouse eggs and grown into early-stage embryos. The embryos were transplanted into the wombs of surrogate mothers.

The Genetic Disaster That Could Result: Faulty Imprinting.  There is a huge genetic time-bomb here.  The genetic phenomenon called imprinting.  This describes the situation where a particular gene is marked or imprinted with a tag that says if it came from the mother or father- and more importantly only one of the other is active.  For example for a particular gene it’s possible that only the maternal copy gene could be active and the copy that comes from the mother could be switched off.  If this process goes wrong (mom and dad copy mistakes) then severe genetic diseases can result. 

A description of imprinting follows and a detailed description is here and here

However, it is now known that the expression of a small number of the 30,000 or so genes in the cells depends on whether the gene copy was passed down from the father or the mother. This process, whereby the expression of a gene copy is altered depending upon whether it was passed to the baby through the egg or the sperm, is called imprinting.

The term “imprinting” refers to the fact that some chromosomes, segments of chromosomes, or some genes, are stamped with a “memory” of the parent from whom it came: in the cells of a child it is possible to tell which chromosome copy came from the mother (maternal chromosome) and which copy was inherited from the father (paternal chromosome). This expression of the gene is called a “parent of origin effect” .

Many reports on-line are coming out about chimeric man-sheep creatures developed.

Scientists have created the world’s first human-sheep chimera - which has the body of a sheep and half-human organs.  The sheep have 15 per cent human cells and 85 per cent animal cells - and their evolution brings the prospect of animal organs being transplanted into humans one step closer.  Professor Esmail Zanjani, of the University of Nevada, has spent seven years and £5million perfecting the technique, which involves injecting adult human cells into a sheep’s fetus.

What is the promise:

He has already created a sheep liver which has a large proportion of human cells and eventually hopes to precisely match a sheep to a transplant patient, using their own stem cells to create their own flock of sheep.

The process would involve extracting stem cells from the donor’s bone marrow and injecting them into the peritoneum of a sheep’s foetus. When the lamb is born, two months later, it would have a liver, heart, lungs and brain that are partly human and available for transplant.

What many don’t realize is that chimeric, transgenic, and xenograpted human-animal research has been going on for some time.  THe genetic research focuses on placing the genes of one species inthe cells of another.  Xenograft research has not gotten much press.  This is what I was extensively involved in.  Here we actually graft human tissue into animals (usually mice) that lack an immune system

My research involved grafting human ovarian tissue into immunodeficient mice and then allowing it to grow, develop, and function.  This ia called a xenograft and the technique has now been developed by several groups.  The hope was to develop techniques to preserve fertility in cancer patients.  There has now been a case reported where human ovarian tissue was frozen, reimplanted (into the woman not a mouse) and resulted in a pregnancy.

The biggest controversies

1. 1. this could potentially lead to a mouse ovulating a human egg that gets fertilized and become a person
   2. there is unknown potential for interactive effects between the species
   3. there is possibility for new animal viral contamination of the human cells that can be transmitted

When I did xenograft research the animals were locked down as if they has Ebola.   Made Alcatraz look like a Holiday Inn.

The top photo is NOT MY RESEARCH —it is a human ear growing on the back of an immunodeficient mouse by a group working on growing human organs for replacement. This is part of the emerging field of tissue engineering where human tissue and even organs are gorwn in lab dishes.  Read more on that subject ere: Creating tissues that can augment or replace injured, defective, or diseased body parts.

Yes, it is real…

The point of this post is not about stem cell research it is about flaws in the peer review process.  However, I need to start with a little timely news and some background first.

In yet another blow to stem cell research, New Scientist reports today that one of the best-known stem cell papers in the past five years, describing adult cells that seemed to hold the same promise as embryonic stem cells is based on likely flawed (or false) data.

Everyone will recall the Korean Stem cell-cloning mess recently. There, Hwang Woo Suk admitted that none of the 11 tailor-made cell colonies he claimed to have created actually exist (and that women were coerced to donate their eggs).  More details of this fiasco are reported here and the retraction of the paper from the journal Science here. 

The latest stem cell mess-scenario seems to be yet another garden variety data falsification.  The new paper prints data that is later found to be exactly used in another paper from the same group but on different cells - (coincidence- methinks not)! 

What’s more interesting to docinthemachine here is the inherent flaws in the peer review system.  Its just like that old bad legal joke:  a jury of your peers means a group of people too stupid or lazy to get out of jury duty (a sad commentary on civic duty and the legal system but hey that’s another post for the politico-blogs).  Unfortunately, the medical peer review process shares some similarities.  I have served as a journal reviewer for many journals and have reviewed original research since I was a resident through fellowship and on as an assistant professor.  I have several disquieting observations. Since I have an extensive network of colleagues, mentors, and mentees (is that a word?) from many different departments and universities (many who just have sought my advice) the following cannot be taken as representative of any particular person I have worked with.  Sorry - not naming names here. 

Where Peer Review Fails:

1) the trickle down review.  A journal reviewer is chosen to review submitted manuscripts based on his past academic accomplishments, expertise in the area of research, and reputation.  However, it is commonplace for academic faculty members, division directors, and departmental chairs to pass the reviews on to junior faculty and fellows-in-training.  On the positive side, when done collaboratively this can be an excellent leaning opportunity for the junior person.  They do extensive research on the topic and prepare an exhaustive report for the senior faculty member who sits down with them and prepares the final review teaching all along the way.  Yes, but we’re not in Kansas anymore Toto!  On the bad side, the lazy senior faculty member passes it on the junior (lacking in the expertise or knowledge) who does his best but does an inadequate job.  The lazy mentor simply says thanks, signs his name, and passes the crap off as his own.  Yep, seen it happen. 

2) The lazy reviewer.  A journal submission goes to more than one reviewer.  Often the reviewers see the comments from the other reviewer.  On many occasions I have completed my review with a dozen points for the author to fix, clarify, or amend.  Sometimes these include very serious research flaws.  Heck, I take the job seriously.  All the more reason I get shocked to see the other reviewer chime back with 2-3 lines of comments, at least one of which is spelling or grammar.  They just did not give it much effort.  This reminds of the couples that come in where the wife speaks little English and the husband translates.  I ask a question, he translates.  She goes on for 5 minutes passionately answering to him- sounds pretty concerned to me.  He turns to me and replies “she says no”.  Something is getting lost in the translation and it’s not accidental.  I remember a seminal paper I wrote along co-authors who are world famous pioneers and leaders in reproductive medicine.  This thing was infamous in my circles since it went through more than 35 major revision drafts over 7 years before my mentor judged it complete.  (for those interested it was a reappraisal of the basic theory of the role of estrogen in human follicular and egg development refuting classical theories - Are Estrogens of Import to Primate/Human Ovarian Folliculogenesis? from Endocrine Reviews and can be found here).  Well I remember my shock when the reviewers comments came back with pages of suggestions!  This guy did MASSIVE research double checking and commenting on minutia in the paper but did 1000% his job as a reviewer (we went on the address all of his concerns). 

3) Bad reviewer choice A.  Some journals have a shortage of good reviewers.  As a result they have a second tier group who just don’t meet the muster in terms of qualifications.  Happens more with very clinically oriented journals.  A related issue is in some of the newer surgical journals.  Many of the leading surgeons on the”cutting edge” (sorry) are amazing pioneers but not necessarily researchers.  Many of the lead academics are amazing researcher but not pioneers in these fields.  Therefore the reviewer tends to be only 1/2 of what’s needed. 

4) Bad reviewer choice B.  The reviewer gets a paper to review that he is really not a expert on.  In the best case he taps out and declines the review.  In the worst case he accepts to do the review but misses a lot.  I have seen this one getting calls “hey Steve- you’re an expert on so and so - I got this paper to review but don’t know anything about this - can you give it a look?”

5) The editor over-ruling the reviewer.  Reviewer finds errors and recommends rejection. Editor accepts the paper and it goes on the be revealed to be a bad study.  Seen it happen.

I even remember a teaching conference we ran briefly when I was at Yale “bad research papers”. We would pull papers that really had flaws and have the fellows comment on what was wrong to teach methodologies etc. 

All in all the medical literature is a living breathing organism.  That’s why internet research by inadequately trained or educated readers can be so faulty.  You can find SOME paper to support both sides of an argument or hypothesis.  A real expert knows them all and weighs the bunch on their merits and methodology to try to come to the best conclusion.  A single paper taken out of its context of the entire literature is just a piece of the puzzle.  If you don’t know research methods and the other studies you are getting set up to draw incorrect conclusions.  This is one of the problems in the courtroom where in expert testimony papers are weighed equally.  It’s the reason why I never draw conclusions on areas where I am not an expert. 

In a sense this is at the basis of the trend towards evidence based medicine.  Instead of just an expert or committee’s opinion research is judged and ranked according to its quality and conclusions drawn and then the results apllied to the individual patient.  It’s a mantra for the modern specialist!  You can read a nice piece on EBM from BMJ here including this definition:

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice. Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients’ predicaments, rights, and preferences in making clinical decisions about their care. By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centered clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens. External clinical evidence both invalidates previously accepted diagnostic tests and treatments and replaces them with new ones that are more powerful, more accurate, more efficacious, and safer

For those wishing to go deep into this area check out extensive resources at UW EMB here and the categories of research levels of evidence here. 

You can read my thoughts about the future of electronic medical research and publishing here.

MORE: great discussion on the flaws of the peer review process on the thread at slashdot.  Obviously over fraud and falsified data is at the top of the crap heap.