Leukocyte InFusion Therapy Begins Clinical Trial Following Cancer 'Cure' In Mice

08-03-05

www.bath.ac.uk/news/articles/releases/tripletcode020805.html

Scientists crack 40-year-old DNA puzzle and point to ‘hot soup’ at the origin of life

A new theory that explains why the language of our genes is more complex than it needs to be also suggests that the primordial soup where life began on earth was hot and not cold, as many scientists believe.

In a paper published in the Journal of Molecular Evolution this week, researchers from the University of Bath describe a new theory which they believe could solve a puzzle that has baffled scientists since they first deciphered the language of DNA almost 40 years ago.

In 1968, Marshall Nirenberg, Har Gobind Khorana and Robert Holley received a Nobel Prize for working out how proteins are produced from the genetic code. They discovered that three letter ‘words’ - known as codons - are read from the DNA code and then translated into one of 20 amino acids. These amino acids are then strung together in the order dictated by the DNA code and folded into complex shapes to form a specific protein.

As the DNA ‘alphabet’ contains four letters - called bases - there are as many as 64 three-letter words available in the DNA dictionary. This is because it is mathematically possible to produce 64 three-letter words from any combination of four letters.

But why there should be 64 words in the DNA dictionary which translate into just 20 amino acids, and why a process that is more complex than it needs to be should have evolved in the first place, has puzzled scientists for the last 40 years.

Dozens of scientists have suggested theories to solve the puzzle, but these have been quickly discounted or failed to explain some of the other quirks in protein synthesis.

“Why there are so many more codons than amino acids has puzzled scientists ever since it was discovered how the genetic code works,” said Dr Jean van den Elsen from the Department of Biology and Biochemistry.

“It meant the genetic code did not have the mathematical brilliance you would expect from something so fundamental to life on earth.”

One of quirks of the genetic code is that there are groups of codons which all translate to the same amino acid. For example, the amino acid leucine can be translated from six different codons whilst some amino acids, which have equally important functions and are translated in the same amount, have just one.

The new theory builds on an original idea suggested by Francis Crick - one of the discoverers of the structure of DNA - that the three-letter code evolved from a simpler two-letter code, although Crick thought the difference in number was simply an accident “frozen in time”.

The University of Bath researchers suggest that the primordial ‘doublet’ code was read in threes - but with only either the first two ‘prefix’ or last two ‘suffix’ pairs of bases being actively read.

By combining arrangements of these doublet codes together, the scientists can replicate the table of amino acids - explaining why some amino acids can be translated from groups of 2, 4 or 6 codons. They can also show how the groups of water loving (hydrophilic) and water-hating (hydrophobic) amino acids emerge naturally in the table, evolving from overlapping ‘prefix’ and ‘suffix’ codons.

“When you evolve our theory for a doublet system into a triplet system, you get an exact match up with the number and range of amino acids we see today,” said Dr van den Elsen, who has worked with Dr Stefan Babgy and Huan-Lin Wu on the theory.

“This simple theory explains many unresolved features of the current genetic code. No one has ever been able to do this before, so we are very excited.”

The theory also explains how the structure of the genetic code maximises error tolerance. For instance, ‘slippage’ in the translation process tends to produce another amino acid with the same characteristics, and explains why the DNA code is so good at maintaining its integrity.

“This is important because these kinds of mistakes can be fatal for an organism,” said Dr van den Elsen. “None of the older theories can explain how this error tolerant structure might have arisen.”

The new theory also highlights two amino acids that can be excluded from the doublet system and are likely to be relatively recent ‘acquisitions’ by the genetic code. As these amino acids - glutamine and asparagine - are unable to hold their shape in high temperatures, this suggests that heat prevented them from being acquired by the code at some point in the past.

One possible reason for this is that the Last Universal Common Ancestor (LUCA), which evolved into all life on earth, lived in a hot sulphurous pool or thermal vent. As it moved into cooler conditions, it was able to take up these two additional amino acids and evolve into more complex organisms. This provides further evidence for the debate on whether life emerged from a hot or cold primordial soup.

“There are still relics of a very old simple code hidden away in our DNA and in the structures of our cells,” said Dr van den Elsen, who points to several aminoacyl-tRNA synthetases - molecules involved in protein synthesis - which only look at pairs of bases in triplet codons, as well as other physical evidence in support of the theory.

“As the code evolved it has been possible for it to adapt and take on new amino acids. Whether we could eventually reach a full complement of 64 amino acids I don’t know, a compromise between amino acid vocabulary and its error minimising efficiency may have fixed the genetic code in its current format.”

A Step Forward In Stem Cell Research

Memorial Sloan-Kettering Cancer Cente

From:  http://www.sciencedaily.com/releases/2005/06/050627005555.htm

June 27 2005

NEW YORK, June 27, 2005 -- According to research published today, investigators from Memorial Sloan-Kettering Cancer Center (MSKCC) have used new techniques in the laboratory that allowed them for the first time to derive unlimited numbers of purified mesenchymal precursor cells from human embryonic stem cells (HESCs). Mesenchymal precursor cells are capable of giving rise to fat, cartilage, bone, and skeletal muscle cells, and may potentially be used for regenerative stem cell therapy in bone, cartilage, or muscle replacement.

The new study, demonstrating the specialized techniques for isolating mesenchymal precursors and generating, purifying, and differentiating those cells in culture, is published online and freely available in the journal PLoS Medicine (Public Library of Science).

Researchers took two lines of completely undifferentiated HESCs and by culturing them in the presence of mouse cells, stimulated them to turn into mesenchymal cells. They then treated these cells with compounds to make them change into specialized bone, cartilage, fat, and muscle cells. According to the study, researchers were able to confirm that these cells were all human cells and that there was no evidence that the cells became cancerous.

Mesenchymal precursors derived from HESCs are different from adult mesenchymal cells because they can efficiently differentiate into skeletal muscle (adult mesenchymal cells do not) in addition to fat, cartilage, and bone. Limited numbers of mesenchymal stem cells have been isolated from adult bone marrow and connective tissues, but harvesting these cells from any of these sources requires invasive procedures and the availability of a suitable donor. The capacity of these cells for long-term proliferation is also poor. In contrast, HESCs could provide an unlimited number of specialized cells.

According to Lorenz Studer, MD, PhD, Head of the Stem Cell and Tumor Biology Laboratory at MSKCC and senior author of the PLoS Medicine study, the high purity, unlimited availability, and multi-potentiality of mesenchymal precursors derived from HESCs will provide the basis for preclinical mouse studies to assess the safety of these cells. The investigators have already taken the next step in this research and are testing the therapeutic potential of embryonic stem cell-derived muscle cells in animal models of muscle disorders.

Stem Cell Therapy Helps Heart Failure Patients

Quito, Jun 7  2005 (Prensa Latina)

Patients with advanced heart failure significantly improved after receiving stem cell therapy, according to results of a clinical trial presented at the annual meeting of the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) in New York.

The study showed, 30 days after receiving the injection of stem cells into their hearts, patients improved an average of 41 percent in their hearts´ pumping efficiency. The distance they could walk nonstop increased by 72 percent in a standard test widely used to assess heart patients.

After 90 days, the heart-pumping improvement was sustained and patients further increased the distance they could walk in the standard test.

The study is the first to use human fetal-derived stem cell therapy in patients with heart failure. Drs. Federico Benetti, Luis Geffner, Yuliy Baltaytis and Teodoro Maldonado at Luis Vernaza Hospital in Guayaquil, Ecuador, performed the surgical procedure.

Advanced heart failure is an incurable and usually fatal condition. Other than heart transplanting, current medical treatments cannot reverse the course of the disease, and only slow its progression or help control its symptoms.

mh/ima/mf

http://antwrp.gsfc.nasa.gov/apod/ap041013.html

New study explains process leading to many proteins from one gene

15 Apr 2005

New findings from researchers at UT Southwestern Medical Center help explain how the 20,000 to 25,000 genes in the human genome can make the hundreds of thousands of different proteins in our bodies.

Genes are segments of DNA that carry instructions for making proteins, which in turn carry out all of life's functions. Through a natural process called "alternative splicing," information contained in genes is modified so that one gene is capable of making several different

proteins. "Alternative splicing is a key mechanism for achieving a diverse range of proteins, which contributes to the complexity of higher organisms," said Dr. Harold "Skip" Garner, professor of biochemistry and internal medicine at UT Southwestern and senior author of a new study aimed at understanding how and why alternative splicing occurs in humans.

The study is available online and will be published in the April 15 issue of the journal Bioinformatics.

Errors in alternative splicing can result in truncated or unstable proteins, some of which are responsible for human diseases such as prostate cancer and schizophrenia, Dr. Garner said. But errors also can result in proteins with new functions that help drive evolutionary changes.

"Alternative splicing appears to occur in 30 percent to 60 percent of human genes, so understanding the regulatory mechanisms guiding the process is fundamentally important to almost all biological issues," said Dr. Garner.

Alternative splicing can be likened to alternative versions of a favorite cookie recipe. If the original recipe (the gene) calls for raisins, walnuts and chocolate chips, and you copy the recipe but leave out the raisins, you'll still get a cookie (protein) from your version, just a different cookie. Omit a necessary ingredient, such as flour, and you'll have a mess (nonfunctioning or malfunctioning protein).

Similarly, the information in genes is not directly converted into proteins, but first is copied by special enzymes into RNA, or more specifically, pre-messenger RNA.

While the entire gene is copied into pre-mRNA, not all of that information will be used to make a protein. RNA segments called exons carry the protein-making information, while the segments between exons, called introns, are snipped out of pre-mRNA by special proteins. Exons also may be snipped out. Once snipping is complete, the remaining exons are spliced back together to form a fully functional, mature mRNA molecule, which goes on to create a protein.

Using computers, the UT Southwestern researchers scanned the human genome and found that the presence of certain DNA sequences called "tandem repeats" that lie between exons are highly correlated with the process of alternative splicing. They found a large number of tandem repeats on either side of exons destined to be spliced out of the pre-mRNA. The tandem repeat sequences also were complementary and could bind to each other.

"The complementary tandem repeat sequences on either side of an exon allow the DNA to loop back on itself, bind together, pinch off the loop containing a particular exon and then splice it out," Dr. Garner explained.

The chemical units that make up an organism's DNA are abbreviated with the letters A, C, T and G. Strings of these letters form genes and spell out genetic instructions. Tandem repeats have DNA sequences with the same series of letters repeated many times, such as CACACACACACA.

Tandem repeats are "hot spots" where errors can easily be made during the copying process; for example, an extra CA could be added or deleted from the correct sequence. These errors could then result in a gene improperly splicing out an exon, thus making the wrong protein, Dr. Garner said. His research group has previously shown that these sequences are highly variable in cancer, and he said the new findings could go a long way toward understanding the genetic nature of how cancers start and progress.

"With this new understanding, we can now predict all genes that can re-arrange in this way and even predict which might splice improperly, resulting in disease," he said.

Former UT Southwestern research associate Dr. Yun Lian was a co-author of the study.

The research was funded by the National Cancer Institute, the National Heart, Lung and Blood Institute and the M.R. and Evelyn Hudson Foundation.

Contact: Amanda Siegfried
amanda.siegfried@utsouthwestern.edu
214-648-3404
University of Texas Southwestern Medical Center at Dallas
http://www.swmed.edu

http://www.medicalnewstoday.com/medicalnews.php?newsid=22857&nfid=mnf

Small Study Suggests Gene Therapy Slows Alzheimer's

POSTED: 8:25 am CDT April 25, 2005

UPDATED: 10:12 am CDT April 25, 2005

WASHINGTON -- The first attempt at gene therapy for Alzheimer's disease patients may show promising results, according to a small study published Sunday in the journal Nature Medicine.

The study suggests gene therapy may significantly slow worsening of the disease in a few people who have tested it so far.

Far more research is needed to see if the experimental treatment, which requires a form of brain surgery, really helps.

But if the approach pans out, researchers said delivering protective substances into a diseased brain may hold the potential to rescue some dying brain cells.

The study shows that in one patient, the brain tissue showed new growth -- which was a first.

Alzheimer's disease is the most common cause of dementia in older people. It's a medical condition that disrupts the way the brain works.

Alzheimer's disease affects the parts of the brain that control thought, memory and language. Although the risk of getting the disease increases with age, it is not a normal part of aging. The cause of the disease is unknown and there is no cure.

It is estimated that currently 4 million people in the United States may have Alzheimer's disease. The disease usually begins after age 65; the risk of Alzheimer's disease goes up with age.

While younger people may have the disease, it is much less common. About 3 percent of men and women ages 65-74 have Alzheimer's disease and nearly half of those over age 85 could have the disease.

Pancreatic cell transplant could lead to diabetes cure

By Anita Manning, USA TODAY

4-18-05

The first successful transplant of insulin-producing cells from a live donor — a mother to her daughter — is being reported today by Japanese scientists, raising hopes for a cure for severe diabetes.

Diabetes experts caution that the procedure has been performed only once and in a patient whose diabetes was not typical. But the accomplishment is "dramatic," says Robert Goldstein, chief scientific officer of the Juvenile Diabetes Research Foundation.

Both the patient, a 27-year-old woman, and her mother, 56, are healthy and have normal blood sugar levels, lead author Shinichi Matsumoto and colleagues say. Their article was posted online Monday ahead of publication in the British medical journal The Lancet. The patient is considered cured for now, but whether the disease will return is uncertain.

The procedure was effective using less than half the mother's pancreas. Transplantation of insulin-producing cells, or islet cells, taken from cadavers may require up to three pancreases, though new techniques have been effective using just one.

"This is a significant advance," says Alan Cherrington of Vanderbilt University, president of the American Diabetes Association. "What it says is that if you can get really healthy undamaged islets, it doesn't take as many of them to cure diabetes as it would if they're subject to some trauma."

If the study's results are duplicated, donations taken from living people could help ease the shortage of such cells, the researchers write. Whether the cells remain viable is unknown, Cherrington says.

Nor is it clear whether the procedure would be as effective in people, like most of those with type 1 diabetes, whose own immune cells have destroyed their insulin-producing pancreatic cells. The Japanese patient's diabetes was caused by chronic pancreatitis, an inflammation, so the risk of an autoimmune attack on the transplanted cells was reduced, the researchers say, and that might have improved her chances.

Diabetes experts also cautioned that the removal of half a pancreas could place the donor at risk of developing diabetes. Only those who have no evidence of prediabetes, obesity or other risk factors could be considered donors, Goldstein says. "It's not like taking out an appendix," he says.

Attempts in the late 1970s to transplant pancreatic cells from living donors failed, partly because the anti-rejection drugs available were "primitive," says James Shapiro of the University of Alberta, a co-author of the article. He pioneered the first successful islet cell transplantation using cells from cadavers five years ago.

"It remains to be seen whether transplant from living donors has same effect," Shapiro says. But "this is the first successful case, and I'm particularly encouraged by the outcome."

King's Achieves UK First in Islet Transplantation

10 Mar 2005

New breakthrough means insulin dependence could be a thing of the past for diabetes sufferers -

A multidisciplinary team at King's College Hospital has successfully achieved islet cell¹ transplantation in a Type 1² diabetes patient. This breakthrough has major implications for diabetes sufferers and has never before been achieved in the United Kingdom. The patient, a 61 year old man, now no longer needs insulin injections, following three transplants of islet cells isolated from cadaveric donor pancreases.

Historically, islet transplants have only been partially successful, in that they have reduced the amount of insulin required, but the need for regular injections still remained. The first reports of insulin independence came recently from a programme in Canada. The King's programme is the first to report a comparable result for the UK. This patient has proved that it is possible for islet transplants to lead to freedom from administered insulin and diabetes treatment associated problems.

The patient suffered from Type 1 diabetes for over 30 years, experiencing increasing problems with his diabetes therapy. Prior to the islet transplant he endured severe, potentially life threatening hypoglycaemic³ attacks, which profoundly affected his quality of life. Following the islet transplant he is now producing his own insulin and is completely free from hypoglycaemia.

The King's team, a collaboration between the Department of Diabetes and the Liver Unit's transplantation team, has to date transplanted three Type 1 diabetes patients with pancreatic islet cells. The first two patients achieved partial success, achieving relief of hypoglycaemia problems, but still requiring small doses of insulin.

Islet cells are obtained from donor pancreases and are transplanted by injection, into the liver of the recipient. Once in the liver, the cells develop their own blood supply and begin producing insulin. This procedure is minimally invasive and only takes around 45 minutes to complete.

There are around 250,000 people in the UK currently suffering from Type 1 diabetes. The patients live with the constant need to be aware of their blood glucose levels and the threat of long term complications such as blindness, renal failure, amputation and cardiovascular disease. Hypoglycaemia is also an ever-present threat. Hypoglycaemia can vary from being mildly uncomfortable to life threatening. People with Type 1 diabetes often live extremely regimented lives, requiring self blood testing four times or more times per day, injecting insulin five times per day and constantly being aware of the food they eat, level of exercise and levels of alcohol consumption.

Professor Stephanie Amiel, Consultant in Diabetes commented: “This breakthough is hugely exciting. The implications for the future are enormous. Eventually, this could mean the end of insulin dependence for all Type 1 diabetes sufferers. In its current state of technology though, islet transplantation is not perfect. We do not have enough organ donors, therefore we cannot extract enough islets to help all Type 1 patients. More research needs to be done to perfect the islet isolation procedures and the drugs we use to prevent rejection of the islets and recurrence of the diabetes. At present we can therefore only offer this treatment to patients, in whom conventional treatments are failing in a major way. However, it is our aim that ultimately all people with Type 1 diabetes would become eligible for islet transplantation and free from insulin dependence.”

Mr Nigel Heaton, Consultant Liver Surgeon, commented: “This breakthrough in islet transplantation is remarkable. King's is the first centre in the UK to achieve insulin independence in Type 1 patients. The research approach at King's is totally multidisciplinary, with experts across specialities in diabetes, liver transplantation, cell isolation and radiology all working together.

“The result of this work will have far reaching implications, not only for Type 1 diabetes patients, but also in the wider area of cell research. We have shown that cell transplantation, with both pancreatic islet cells and previously with hepatocyte cells, can offer patients a valuable alternative to conventional treatments.”

The islet cell research has been funded by King's College Hospital Charitable Trust and Dixons Charitable Foundation. The clinical costs are supported by Diabetes UK.

Jo Brodie, Islet Project Coordinator, Diabetes UK commented: ‘We're delighted this procedure has been such a success. To have someone with Type 1 diabetes completely insulin free is a fantastic achievement. Diabetes UK has always believed that islet research could provide a cure for Type 1 diabetes. We continue to fund islet research in the UK and hope many more people will be able to have this pioneering treatment.'

Notes to Editors

1. Islet cells are found in the pancreas and produce insulin

2. Type 1 diabetes often starts in childhood and once present is irreversible. It occurs as a result of the cells in the pancreas that produce insulin being destroyed. Usually, the destruction of the insulin making cells is the result of an autoimmune process, in which the body fails to recognise the cells as its own and destroys them. This destruction results in total insulin deficiency. Prior to this breakthrough the only treatment for Type 1 diabetes was insulin injections.

3. Hypoglycaemia is a condition where by blood glucose falls to a dangerously low level during the daily course of insulin therapy. If the blood glucose falls until it reaches a point where it is too low to support normal brain function, then confusion, abnormal behaviour, and aggression can result. If nothing is done, eventually glucose levels fall so low and brain function is so abnormal that unconsciousness and seizures can occur, ending in coma. Such episodes of severe hypoglycaemia are more common in people who have suffered from diabetes in excess of 15 years and in people who are attempting very tight glucose control in order to prevent the other long term complications of diabetes.

4. In 2003 a breakthrough in hepatocyte (liver) cell research was announced at King's. Hepatocyte cells transplanted into the diseased livers of patients with particular conditions were found to act as a bridge to transplantation - keeping the patient alive until a suitable donor liver could be found. Hepatocyte transplants were also found to negate the need for a whole organ transplants in some patients by creating healthy new cells in failing livers. There is an important link with the islet research programme in that both require the precise and controlled isolation of cells from donated organs so that the recipient patient receives only an infusion of active cells rather than needing to undergo the major surgery of full organ transplant. This research continues.

King's College Hospital

Possibility of Growing New Teeth Envisioned

NEW YORK (Reuters Health) - We may not be very far away from a time when dentists offer to help people with damaged or missing teeth grow new ones, according to new research presented on Wednesday.

A series of presentations at a dental meeting demonstrate that techniques using stem cells and gene therapy to regenerate teeth are producing promising results, suggesting this technique may not be far off.

"I think it's looking like quite an exciting technology for the near future," said Dr. Tony Smith, editor of the Journal of Dental Research, who was not involved in any of the newest studies.

Smith explained that the presentations describe techniques that enable dentists to coax existing teeth into repairing and regenerating themselves, and techniques where dentists can "start from scratch."

Clearly, techniques that involve adding new tissue to already-existing teeth are "probably a bit closer on the horizon," perhaps within a "handful of years," Smith predicted. Techniques that grow teeth from scratch will likely take at least another 10 years to perfect, he added.

In some instances, researchers are trying to reprogram cells in the mouth to behave like tooth-growing cells, convincing them they have to produce new teeth, Smith explained.

Other techniques being explored involve using stem cells, which have the potential to become any type of cell or tissue. In one study being presented at the meeting, researchers successfully extracted stem cells from the pulp of adult teeth, Smith said. The next step is to examine whether it's possible to use these teeth to regenerate new dental tissue, he said.

Other research being unveiled describes tests of different approaches to select stem cells from pulp, and all shows "different degrees of success," Smith said.

These techniques may one day help people whose teeth have decayed from very bad cavities, who have lost teeth in an accident, or whose teeth have worn down from acid or hard brushing, among other conditions, he predicted.

The findings are being presented Wednesday, Thursday and Saturday during the 83rd General Session of the International Association for Dental Research in Baltimore, Maryland.

© Copyright Reuters Ltd. All rights reserved. The information contained In this news report may not be published, broadcast or otherwise distributed without the prior written authority of Reuters Ltd.

Human Stem Cells Become Nerve Cells in Study

Sun Jan 30, 2005 02:07 PM ET

WASHINGTON (Reuters) - Stem cells taken from human embryos were coaxed into becoming motor neurons in an experiment that might one day help scientists repair damaged nervous systems, researchers reported Sunday.

The study supports claims by stem cell researchers that they can train embryonic stem cells to develop on demand into any type of tissue in the body.

They hope this technology will eventually transform medicine and allow cures for a range of diseases -- in this case, nervous system injuries and diseases such as Lou Gehrig's disease.

The team at the University of Wisconsin used stem cells that are approved for research by the federal government. Their experiment was funded by the National Institutes of Health and the Amyotrophic Lateral Sclerosis Association, which is seeking a cure for the untreatable and paralyzing condition also known as Lou Gehrig's disease.

Su-Chun Zhang and colleagues said their trial-and-error study helped them learn how motor neuron cells, which are key to the nervous system, develop in the first place.

Motor neurons transmit messages from the brain and spinal cord and help control almost every movement in the body.

Patients with motor neuron diseases or spinal cord injuries lose control of these movements.

The hope is to repair or replace these damaged cells.

Writing in the journal Nature Biotechnology, Zhang and colleagues said they delivered a carefully timed cocktail of proteins to their cells to direct their development.

"You need to teach the (cells) to change step by step, where each step has different conditions and a strict window of time," Zhang said in a statement. "Otherwise, it just won't work."

And Zhang said the experiment showed that human stem cells do not necessarily differentiate in the way that other animal stem cells do.

"We cannot simply translate studies from animal to humans," Zhang said.

The administration of President Bush does not support the use of human embryonic stem cells except in limited circumstances using cells already in existence as of 2001. Federal funds may not be used to take new stem cells from human embryos, which are destroyed in the process.

Opponents of human embryonic research say this is tantamount to murder, while supporters say embryos from fertility clinics are slated for destruction anyway and point to the potential benefits from research.

© Reuters 2005. All Rights Reserved.

Study Shows Stem Cells Can Preserve Vision

11/18/04 -- For the first time researchers have shown that transplanted stem cells can preserve and improve vision in eyes damaged by retinal disease. In the cover article in the November 2004 Investigative Ophthalmology and Visual Science, scientists from Harvard’s Schepens Eye Research Institute describe results of a mouse study in which transplanted stem cells develop into retinal cells, prevent the death of “at risk” retina cells in the recipient mice and improve the vision of treated mice. “These findings hold great promise for potential treatments for people suffering from macular degeneration, diabetic retinopathy and other retinal diseases,” says Michael Young, PhD, an assistant scientist at Schepens Eye Research Institute and the lead author of the study.

The retina is a tissue-thin membrane at the back of the eye responsible for sending light and images from the outside world through the optic nerve to the brain, which interprets them. The retina contains light sensitive cells, known as rods, which make it possible for us to see in black and white and in low light, and cones, which are responsible for color and high-acuity vision. In diseases such as macular degeneration, it is these cells that are being destroyed.

Believing that stem cells - cells that have the capacity to change into other kinds of cells - could potentially save vision, Young and his team decided to test their theory in mice. They transplanted retinal stem cells from young “green” mice into the eyes of normal-colored mice that had retinal disease. Green mice are genetically raised so that all their tissues are fluorescent green. The green color makes it possible to detect where the transplanted cells are and how they are growing and changing.

After several weeks the team evaluated the eyes of the treated mice and found that the green cells had migrated to where they were needed in the damaged retina and had changed into what looked like normal retinal cells. The scientists also found that many of the cone cells that were on the verge of dying before the transplant appeared to regain or retain their function. The researchers speculated that the transplanted cells were secreting a factor or substance that saved these fragile cells. (There is growing evidence that rod cells keep cone cells alive by secreting a special factor)

To test whether the mice with transplanted stem cells could see better, the team then placed them and the control mice (without the transplants or with non-stem cell transplants) in dark cages and flashed a series of increasingly lower level lights at both groups over a period of time. Mice are photophobic and stop their normal activity when they detect light. The researchers took advantage of this natural response and found that the mice with the transplanted tissue continued to respond to the light as it reached the lowest levels. The control mice did not.

“These are the first steps toward the use of stem cells for saving existing vision and then—down the road—restoring vision that has already been lost,” says Young, who believes that stems cells will have many roles to play in the fight against blinding diseases. Young and his team are now investigating the same phenomenon in pigs, whose eyes are larger and more like human eyes.

Source: Schepens Eye Research Institute

Unravelling of human code paves way for new treatments

JAMES REYNOLDS
SCIENCE CORRESPONDENT

Scotsman.com  21st  October,  2004

TAILORED therapies to target a range of diseases, such as diabetes and breast cancer, may be a step closer after the final draft of the gene-rich part of the "human book of life" was published yesterday.

The sequence provides a blueprint of the genes that make life possible and is accurate to only one error in 100,000 "letters" of code, an article in the journal Nature reveals.

Analysis of the new data shows that the human genome, which is the entire genetic map of an organism, contains between 20,000 and 25,000 genes. Surprisingly, the number of genes is possibly only 5,000 more than that of the nematode worm, one of the simplest organisms on the planet.

Of the genes that have been identified, 1,183 were only recently discovered by a process known as "gene duplication".

Scientists also found that 37 genes seem to have recently "died" by developing a mutation that made them non-functional, although it does not affect human development.

The work, which was conducted by the International Human Genome Sequencing Consortium (IHGSC), builds on the historic publication of the first draft of the whole human genome in 2001. The publicly funded IHGSC and the private company Celera announced completion of the first drafts in jointly published papers three years ago.

However, the drafts were some way off being perfect, as both groups were missing about 10 per cent of what is known as the "euchromatin" - the crucial gene-rich portion of the genome.

Genes are sequences of DNA that provide the coded instructions for making proteins. Other parts of the genome consist of DNA but not genes.

Dr Jane Rogers, the head of DNA sequencing at the Cambridge-based Sanger Institute, which conducted much of the work for the first draft in 2001, explained: "What we find in the human genome is that the majority of it is made from a fairly unique gene-containing sequence, and this is what is known as the euchromatic part.

"That holds the information that provides the codes for proteins and the regulation of their production. This is important because it provides most of the instructions to make the materials that we humans consist of."

The sequence, published throughout the world yesterday, is estimated to cover 99 per cent of the gene-containing part of the genome. It has just 341 gaps remaining and consists of unbroken runs of code averaging 38 million bases - the chemical "letters" that make up DNA.

The IHGSC scientists wrote in Nature: "The genome sequence reported here should serve as a firm foundation for biomedical research in the decades to come.

"It allows systematic searches for the causes of disease - for example, to find all key heritable factors predisposing to diabetes or ... mutations underlying breast cancer - with confidence that little can escape detection."

Dr Rogers

wrote: "That this draft is again missing a small portion of the euchromatin does not mean that the information is unusable.

"Making this sequence available to researchers from the outset has really stimulated biological exploration and changed the way that researchers carry it out.

"So instead of starting with needing to identify a piece of DNA that has an effect, they will actually go to the database first and look for the sequence and start their experiments from there.

"Small pieces are still missing throughout the genome, and it is of the utmost importance that we now try and find those.

"We are now trying to define where variations occur in the human genome that we can then say are causative for disease. If we can do that reliably, that would then allow us to look in populations of people who have specific diseases and see if we can observe the changes that occur in the genome.

"If we do see the changes it will then tell us if it is the reason for the disease. There is some prospect in future for the potential for gene therapy if we need to replace a gene, and there are many more opportunities as well. For example, if we have a mutation that affects some sort of metabolising enzyme, a patient might not respond to one type of drug very well, but they could respond to another. Having that information could direct the prescription of drugs to be far more effective."

Professor Robin Lovell-Badge, the head of developmental genetics at the National Institute for Medical Research in London, wrote: "This will greatly increase our understanding of what happens in cases of genetic disease and issues about interaction between genes and environment.

"If you take heart disease or certain types of diabetes, people who suffer from strokes and even behavioural problems, these are all likely to be influenced by a combination of different genes. Knowing what the full set of genes are is an incredibly useful starting point to gaining knowledge of what causes those ailments.

"We can also begin to discover why some people respond well to certain drugs, and others do not, which is clearly influenced by genetics.

"All these things will be enormously helped by having the full sequence, as it used to take years to find a single gene responsible for conditions such as cystic fibrosis. Now we can just consult the database."

In an accompanying article, Dr Lincoln Stein, from the Cold Spring Harbor Laboratory in New York, said the finished gene sequence had roughly doubled the total time and cost of the human genome project.

He wrote: "Does it contribute anything new to our understanding of the genome? It does indeed, and to prove the point the authors of the current paper describe several large-scale analyses of the genome that would have been difficult to perform on the draft sequence. Absolute completeness [of the sequencing project] will be elusive, but ... obtaining the substantial majority of the information will greatly accelerate the pace of biomedical research in thousands of laboratories."

Dr Stein concluded: "In sequencing the human genome, the researchers have already climbed mountains and travelled a long and winding road.

"But we are only at the end of the beginning: ahead lies another mountain range that we will need to map out and explore as we seek to understand how all the parts revealed by the genome sequence work together to make life."

In an accompanying Nature paper, scientists led by Dr Evan Eichler, from the University of Washington in Seattle, said the new sequence showed up shortcomings in the technique used by Celera.

The company took a controversial shortcut called the "whole genome shotgun method", which involved blasting apart the genome, sequencing random fragments, and using a computer to fit them together like pieces of a jigsaw puzzle.

Dr Eichler’s team found that the technique missed many duplicated DNA regions and may not provide an accurate picture of the genome.

Much of our DNA is disposable, study suggests

MICE, and probably humans, can survive despite having whole pages of DNA ripped out of their "book of life", scientists claimed yesterday.

Researchers deleted more than two million bases - the chemical "letters" of the DNA code - from the mouse genome. To the surprise of the scientists, the mice shrugged off the loss and were virtually unaffected.

The deleted sequences were from regions of the genome not known to have any essential function. Eddy Rubin, the director of the Joint Genome Institute in Walnut Creek, California, where the work was carried out, said: "We were looking particularly for sequences that might not be essential. Nonetheless, we were surprised, given the magnitude of the information being deleted from the genome, by the complete lack of impact noted.

"From our results, it would seem that some non-coding sequences may, indeed, have minimal, if any, function."

Controversy surrounds the DNA "desert" that makes up 98 per cent of the human genome.

Genes are sequences of DNA that provide the essential instructions for making proteins. But large swathes of DNA exist between the genes that appear to be barren wasteland with no purpose.

Some experts believe this "junk" DNA may not be as useless as it seems and plays a hidden role. But the new research, published in the journal Nature, indicates that large parts of the genome really are disposable.

Genetic basis for metabolic diseases detected

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