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"Human embryonic stem cells created from adult tissue for first time," The Guardian reports, while the Daily Mail's front page leads with the somewhat fanciful warning that new research raises the "spectre of cloned babies".

These headlines are based on newly published research into the use of a technique known as somatic cell nuclear transfer (SCNT) as part of embryonic stem cell research. It should be noted that no babies were born as a result of this research, and the researchers had no intention of producing a live cloned human being.

SCNT involves taking donated egg cells from women and removing their genetic material. These are then fused with human cells – in this case skin cells – and the fused cell begins behaving in a similar way to an embryo by producing human stem cells.

This research is the first time the technique has been successful using human cells.

When these stem cells were tested, researchers found that the cells were able to develop into other types of cells in a manner similar to that seen in stem cells derived directly from embryos.

The researchers say that this could have exciting implications. The technique could potentially be used to take skin cells from a patient to create "personalised" stem cells. The resulting stem cells could then possibly be used to repair damaged tissue, or even treat genetic conditions.

However, there remain ethical concerns over the implications of using SCNT to develop stem cells. These concerns, as well as scientific and financial considerations, will need to be taken into account as this field continues to develop.

  

Where did the story come from?

The study was carried out by researchers from Oregon Health and Science University (OHSU) and Boston University School of Medicine in the US, as well as Mahidol University in Thailand. It was funded by OHSU, the Leducq Foundation and the US National Institutes of Health, and was published in the peer-reviewed journal, Cell.

Media coverage of this study was as varied as people's feelings are about stem cell research. It ran from the medically hopeful headline of The Independent ("Human cloning breakthrough raises hopes for treatment of Parkinson's and heart disease"), to a straight-to-the-facts headline from The Guardian ("Human embryonic stem cell created from adult tissue for first time"), to fear and controversy from the Daily Mail ("New spectre of cloned babies: Scientists create embryos in lab that 'could grow to full term'").

Despite its headline and further warnings of "designer babies", the Daily Mail does provide a quite useful figure outlining the process the scientists used in the research.

 

What kind of research was this?

This was a laboratory study that aimed to produce embryonic stem cells from adult skin cells. Embryonic stem cells are unique in that they are able to develop (or differentiate) into other types of cells. Because of this, it is thought that they could play a critical role in the treatment of a wide variety of diseases.

Researchers have been looking into ways of using a patient's own cells to create embryonic stem cells, as this would ensure that the genetic material in any cells used therapeutically would match the patient's DNA. In theory, this should prevent the body from rejecting the cell.

The researchers report that previous attempts to produce embryonic stem cells using this technique have failed, as the cells stopped dividing before they reached an advanced enough stage. During their experiments, researchers identified two reasons for this inability to sufficiently grow the cells and developed techniques to overcome these limiting factors.

Laboratory studies are necessary for developing techniques and procedures that may one day lead to new medical therapies.

This study will no doubt be very exciting for researchers working with stem cells, but we're still a long way from the findings of this study being translated into new treatments for conditions such as Parkinson's disease or heart disease.

 

What did the research involve?

The researchers used a technique called somatic cell nuclear transfer (SCNT) to transfer genetic material from adult human skin cells into a human egg cell in order to produce embryonic stem cells. SCNT has been used to clone animals before, and is thought to have potential applications in the study and treatment of human diseases.

SCNT involved taking the nucleus (the part of a cell containing most of the genetic information) from a person's skin cells, inserting its cells into a donor's unfertilised egg cell that had its nucleus removed. The skin cell nucleus was then fused with the donor egg cell. Once this happened, the person's genetic material was in a vehicle that was theoretically able to divide.

Researchers then optimised methods to prompt the egg cell to start and continue to divide using electricity and chemical compounds, including caffeine.

Once this cell division yielded approximately 150 cells – a stage called a blastocyst – researchers were able to isolate the embryonic stem cells. The researchers then tested these stem cells to see if their genetic material retained any traces of the genetic material from donor egg cell's nucleus. They also tested whether or not the embryonic stem cells were able to develop into other types of cells.

 

What were the basic results?

The researchers were able to use SCNT to generate human embryonic stem cells. These cells were found to match the nuclear genetic material of the person's skin cells, and did not contain any trace of the donor egg's nuclear genetic material.

The embryonic stem cells were able to develop into several different types of cells, including heart cells. They were also found to express genes similar to those expressed by embryonic stem cell lines derived following IVF procedures, which the researchers referred to as "genuine" embryonic stem cells.

 

How did the researchers interpret the results?

The researchers say that this study represents the first successful attempt at generating human embryonic stem cells following somatic cell nuclear transfer.

They say that the observed ability for these embryonic stem cells to develop into heart cells demonstrates their potential use in regenerative medicine.

 

Conclusion

This research represents the first time that human embryonic stem cells have been developed using the "cloning technique" known as somatic cell nuclear transfer (SCNT).

It is important to note that this study did not attempt to clone a human being by creating a baby in a lab. It is unclear at this point whether the cells in this study would continue to stably divide in a manner sufficient for an embryo to develop to full-term.

While this study is certainly a breakthrough for researchers in the field, its findings are unlikely to translate quickly into regenerative medicine or other medical therapies.

There are some scientific limitations to the approach, including the fact that only a fraction of the fused cells were able to divide sufficiently to reach the blastocyst stage and, of those that did, not all were able to generate stable embryonic stem cell lines.

It is also worth considering that donated egg cells from women are required before SCNT can be carried out, potentially limiting the ability of scientists to generate stem cells on an "industrial" basis.

SCNT does not represent the only approach to embryonic stem cell development. Researchers around the world continue to investigate several methods for developing and using stem cells. It is not immediately clear how the current research will fit into this field, or whether it will trigger a major shift in stem cell research.

In addition to these scientific hurdles, there are ethical and financial considerations that will likely need to be addressed.

Despite these issues, this research does represent a breakthrough in the use of SCNT in the stem cell research field and has implications for disease research.

What the study emphatically does not represent is an impending expansion into cloning babies.

 

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links To The Headlines

Human embryonic stem cells created from adult tissue for first time. The Guardian, May 15 2013

Embryonic stem cells: Advance in medical human cloning. BBC News, May 15 2013

New spectre of cloned babies: Scientists create embryos in lab that 'could grow to full term'. Daily Mail, May 15 2013

Cloning breakthrough by US scientists. The Daily Telegraph, May 15 2013

Stem Cells Made From Cloned Human Embryos. Sky News, May 15 2013

Cloned babies fear as stem cells are created from skin. Daily Express, May 16 2013

Links To Science

Tachibana M, Amato P, Sparman M, et al. Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer. Cell. Published online May 15 2013

“Double drug hope for brittle bone sufferers”, reports the Daily Mail.

This headline follows a small but well-designed trial of treatments for postmenopausal osteoporosis. As women go through the menopause, levels of the hormone oestrogen begin to fall. This drop in oestrogen can lead to a thinning and weakening of the bones, increasing the risk of broken bones (fractures).

While current treatments can help prevent further weakening of the bones, they are not particularly effective at restoring bone strength – known as bone mineral density (BMD). In this study, researchers found that using a combination of teriparatide (Forsteo) and denosumab (Prolia) led to a significant improvement in BMD, when compared to using either medicine on its own.

While this research is encouraging, there are still questions that need answering. For instance, it isn’t clear whether this combination treatment is effective at preventing fractures (more participants would be required) or safe past 12 months (the length of this study).

Similarly, the research was mainly in white, city-dwelling postmenopausal women, so the effectiveness may differ in women from different places and ethnic backgrounds. Similarly, it is not clear whether it would benefit men with osteoporosis (which is less common, but still accounts for roughly 20% of cases).

Aside from these limitations, this research is a positive step forward in the search for new treatment options for osteoporosis. The encouraging results are likely to lead to further, larger studies.

 

Where did the story come from?

The study was carried out by researchers from at the Massachusetts General Hospital, Boston (US) and was funded by the National Center for Research Resources as well as the pharmaceutical manufactures Amgen and Eli Lilly.

Amgen manufactures denosumab and Eli Lilly manufactures teriparatide.

However, the publication states that the funders of the study had no role in study design, data collection, data analysis, data interpretation, or the writing of the report.

The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

The study was published in the peer-reviewed medical journal The Lancet.

The media reporting generally described the research findings accurately although discussion about the limitations of the research was minimal.

 

What kind of research was this?

This research used a randomised control trial (RCT) to test whether combining two approved osteoporosis medicines (teriparatide and denosumab) would improve bone mineral density in postmenopausal women.

Osteoporosis is a condition that affects the bones, causing them to become weak and fragile and more likely to break (fracture). These fractures most commonly occur in the spine, wrist and hips, but can affect other bones such as the arm or pelvis. Approximately 3 million people in the UK are thought to have osteoporosis. Although commonly associated with postmenopausal women, osteoporosis can also affect men, younger women and children.

The two drugs, teriparatide and denosumab, are already used individually to treat osteoporosis but they work in slightly different ways. So the researchers wanted to test whether there was any added benefit of using the two drugs together.

Despite drugs being available for osteoporosis, the researchers’ say no currently approved treatment actually restores normal bone density in most patients with osteoporosis – they merely halt the decline. And options for those with severe osteoporosis are limited; the resulting risk of fracture, aside from affecting people’s quality of life, puts a considerable strain on the NHS. It is estimated that there are around a quarter of a million fractures each year in the UK. This means there is a continual need for new or improved treatments.

An RCT is one of the most reliable ways of testing whether a new drug, or in this case combination of drugs, is effective.

 

What did the research involve?

Between September 2009 and January 2011 the researchers enrolled 100 postmenopausal women (aged 45 years or older, with at least 36 months since last period) with osteoporosis who were at high risk of bone fracture. Women were enrolled through a mailing advertisement and on referral to Massachusetts General Hospital in Boston (US).

Bone mineral density is measured by ‘T-score’ and is simply the number of units, known as standard deviations, above or below the expected average for a healthy 30-year-old adult of the same sex and ethnicity as the patient. Only about 2.5% of women would have a T-score less than -2.0, for example.

The researchers defined high fracture risk as either:

• T-score –2.5 or less at the spine, hip, or femoral neck
• T-score –2.0 or less with at least one risk factor; fracture after age 50 years, parental hip fracture after age 50 years, previous overactive thyroid, inability to get up from a chair with arms raised, or current smoking
• T-score –1.0 or less already with history of a fracture from osteoporosis

Women were split into three equal groups to receive 20 microgram teriparatide daily, or 60 milligram denosumab every six months, or both.

Bone mineral density was measured at 0, 3, 6, and 12 months. This included measuring bone density at the lumbar spine, hip bone and neck of the femur using low-dose x-rays and bone biomarkers. Calcium intake (which can influence bone strength) was also recorded at the start of the study through a food frequency questionnaire.

Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. Physicians interpreting bone mineral density assessments and the laboratory staff doing bone-marker assays were unaware of patients’ treatment groups.

The analysis compared changes in bone density from baseline (the start of the study) to the different time points (3, 6, and 12 months) for each of the different locations (spine, hip bone, and neck of femur).

 

What were the basic results?

Of the 100 eligible women, 94 completed the 12 month study. At 12 months, the main findings were that:

• Lumbar spine bone density had increased significantly more in the combination group (9.1%, standard deviation (SD) 3.9) than in the teriparatide (6.2%, SD 4.6) or denosumab (5.5%, SD 3.3) groups.
• Femoral-neck bone density also increased more in the combination group (4.2%, SD 3.0) than in the teriparatide (0.8%, SD 4.1) and denosumab (2.1%, SD 3.8) groups.
• Total hip bone density also increased more in the combination group (4.9%, SD 2.9; teriparatide, 0.7% SD 2.7; denosumab 2.5%, SD 2.6).

All these results were statistically significant.

 

How did the researchers interpret the results?

The researchers concluded that, “combined teriparatide and denosumab increased bone mineral density more than either agent alone and more than has been reported with approved therapies.” Furthermore, “combination treatment might, therefore, be useful to treat patients at high risk of fracture.”

 

Conclusion

This small but well-conducted RCT showed that combining licensed osteoporosis medicines teriparatide and denosumab may increase bone density more than either medicine used on their own, in postmenopausal women at high risk of bone fracture.

The researchers highlighted that their results were not consistent with previous trials looking at combination therapies for osteoporosis, which found no benefit of combining them.

However, previous research did not use the same combination of medicines in the same dose as the present trial. It could be the case that the dosages used in previous research were not given at the optimal level.

And while the study showed statistically significant differences in bone density at 12 months, this does not necessarily mean the treatment lead to a reduced rate of fractures – which is the ultimate aim of treating osteoporosis. Larger, longer-term studies are required to see what impact this combination treatment has on fracture risk, as well as assessing how safe and effective both drugs are in the longer-term.

This is particularly relevant because teriparatide is only licensed to be used for a maximum of 24 months (a point the Daily Mail usefully highlighted). It remains to be seen what would happen when this combination of therapies were stopped – would the benefits be reversed, and would it be safe to continue using the medicine longer than recommended?

These issues would need to be thoroughly addressed before this potentially useful combination could feasibly be routinely used in the NHS.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on twitter.

Links To The Headlines

The double drug hope for brittle bone sufferers. Daily Mail, May 15 2013

Links To Science

Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. The Lancet. Published online May 15 2013

 

"Depressed people are out of sync with the rest of the world because their body clocks are broken," reports the Mail Online website, while The Independent claims that depressed people live in a "different time zone".

The story comes from a study that looked at the activity of genes thought to be involved in regulating the body's internal clock – the innate sense that most people have of the changes over a 24-hour day to night cycle (circadian rhythms).

Researchers did a detailed study of gene expression, the effect that certain proteins contained inside individual genes have on genetic activities inside the body.

The study involved examining brain tissue taken from people who donated their brains to science after their deaths. Of the sample, 55 people had no history of psychiatric illness, while 34 patients had a history of severe depression (major depressive disorder, or MDD).

Researchers found that the gene activity associated with regulating circadian rhythms was much weaker, and often disrupted, in the brains of patients who had MDD.

These results possibly present, as philosophers put it, a "causality dilemma" (a chicken and egg problem) – does depression lead to a disrupted body clock, or does a disrupted body clock make people vulnerable to depression?

It is too early to say what help these findings may be in the understanding and treatment of MDD.

 

Where did the story come from?

The study was carried out by researchers from the University of Michigan, the University of California, Weill Cornell Medical College, Stanford University and the HudsonAlpha Institute for Biotechnology, and was supported by the Pritzker Neuropsychiatric Disorders Research Fund.

It was published in the peer-reviewed Proceedings of the National Academy of Sciences.

Both the Mail Online and The Independent covered the research uncritically. Given the specialised nature of this research, it's not surprising that both of the news stories appeared to be strongly based on an accompanying press release and were not a critical appraisal of the study itself.

 

What kind of research was this?

This was laboratory research using donated post-mortem brains. In it, researchers analysed in detail the gene expression of certain genes thought to be associated with circadian rhythm regulation at the time of death.

The authors point out that a common symptom of major depressive disorder is the disruption of circadian patterns, which can trigger symptoms of insomnia as well as excessive daytime sleepiness and fatigue (feeling tired all the time). However, to date there is no direct evidence of "circadian clock dysregulation" in the brains of patients with major depressive disorder.

 

What did the research involve?

Researchers used human brain tissue taken from a US donor programme with the consent of next of kin. They also took information from medical records, medical examiners and interviews with relatives to record the donors' previous physical health, medication use, psychiatric problems, substance use and details of death.

This was done in order to assess whether donors had a major depressive disorder, a severe form of depression that has a significant impact on day-to-day living.

They also assessed whether physiological stress at the time of death would have had an effect on gene expression, and took account of this potential confounding factor.

Researchers analysed the brain tissue of 55 donors with no history of psychiatric or neurological illness and 34 patients with major depressive disorder. Using specialist techniques called DNA microarray, they measured the expression of genes thought to be associated with regulating circadian rhythms in different areas of the brain.

They used the control group to build a detailed picture of circadian gene expression in brain tissue and compared the results with those found in the brains of people with MDD. They also used the rise and fall of the top 100 "cyclic" genes in 60 of the donors to predict the time of death in all the others, both cases and controls. 

 

What were the basic results?

In the brain tissue from donors without major depressive disorder, they found that the activity of "circadian" genes at certain times of the day and night was consistent with data derived from other diurnal (day-active) mammals. More than 100 genes showed "consistent cyclic patterns" over six brain regions.

However, in the brains of patients with MDD gene expression of cyclic patterns was far weaker and more disrupted, with the patients' day pattern of gene activity often resembling a night pattern.

They found that predictions of time of death were more accurate among controls than for those with MDD.

 

How did the researchers interpret the results?

The researchers say the results provide convincing evidence that there is a "rhythmic rise and fall" in the activity of hundreds of genes in the human brain associated with regulating the day/night cycle. There is also evidence that the activity of genes associated with circadian rhythms is abnormal in people with MDD.

The study identifies hundreds of genes in the human brain that are likely to be involved in the sleep/wake cycle. The researchers conclude that daily rhythms in these genes are "profoundly dysregulated" in MDD. They say the results pave the way for the identification of new biomarkers and treatments for mood disorders.

 

Conclusion

This study is of interest, but at the moment it has little bearing on our understanding and treatment of depression. It could lead to new insights and treatments in the future, but there is no guarantee that this will be the case.

Also, as the authors point out, gene activity can result from many factors, including disease and drug history. In particular, it should be pointed out that:

• the researchers relied on only 55 patients to build a "normal" picture of genetic expression associated with the sleep/wake cycle
• it is not clear whether those in the MDD group had all been formally diagnosed with MDD or how long they had had depression, and it is possible there were errors in the classification of patients either with or without MDD

In conclusion, it is too early to say whether this study's findings might help in the understanding and treatment of major depressive disorders.

 

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links To The Headlines

New forensic technique for estimating time of death by checking internal clock of the human brain. The Independent, May 13 2013

Out of sync with the world: Depressed people suffer with 'broken body clocks'. Mail Online, May 14 2013

 

Links To Science

Zi JZ, Bunney BG, Meng F, et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. PNAS. Published online May 13 2013