Scientists Map Entire DNA of Human Fetus

December 10, 2010


Parents may soon be able to find out if their unborn child is prone to any inherited diseases, researchers said on Thursday, after developing a non-invasive technique to draw the entire gene map of the human fetus.

By analyzing a sample of the mother’s blood, which contains DNA from the fetus, scientists in Hong Kong and the United States were able to identify all the DNA strands that belong to the child and piece them together.

“Before this work, people only could look for one disease at one time but now you can construct a screen for a number of diseases which are prevalent in any particular population,” said lead author Dennis Lo, professor of medicine from the Chinese University in Hong Kong.

The research team’s breakthrough was discovering that the mother’s plasma holds the entire fetal genome. Previously, only part of the baby’s DNA was thought to be in the mother’s blood.

“Now that we know (the) entire fetal genome is in there, you can look for any disease that is genetically inherited.”

The study, published in the journal Science Translational Medicine on Thursday, recruited a couple undergoing prenatal diagnosis for a hereditary blood disorder, beta-thalassemia.
“In the mother’s blood, 90 percent of the DNA is her own … and 10 percent is the baby’s. Half of the fetal genome is from father and half from mother,” Lo said.

Lo described the process as akin to putting together a jigsaw puzzle with millions of pieces — only in this case, 10 times as many pieces from a much larger jigsaw were mixed in with it too.

“The whole genome is fragmented into millions of pieces and by this exercise, we assemble it back,” Lo said.
“It’s like assembling a jigsaw puzzle with millions of pieces. But to make it more challenging, you mix in 10 times (the number of pieces) from another jigsaw puzzle, that’s the mother’s own DNA. And you are trying to assemble the child’s.”

Experts who were not involved in the study called for caution.

“It is too early to apply the technology widely as we are not yet able to interpret many of the results that can be generated accurately,” said Christine Patch, chair of the British Society for Human Genetics. “We do not randomly test pregnancies for a long list of … conditions that may only manifest in adult life on the basis that individuals may not want to know that information when they are older.”

Testing a future

February 9, 2010

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Last Tuesday the Lurias in Hassenfeld Conference Center had a different feel than usual. Instead of having empty chairs and tables, students were seated against the wall waiting in line or moving table to table to answer questions about their genetic histories. Next, students moved to to a table to have a blood sample taken. In four weeks, these students will know what genetic diseases they might carry.

Dr. Harry Ostrer, the geneticist behind the testing, came to Brandeis with a team of assistants from New York University to conduct free genetic tests on students of Jewish heritage. Ostrer, who has a distinctively dark mustache, specializes in studying diseases that affect Ashkenazi Jewish populations.

Ostrer and his team have been traveling to various college campuses across the United States to offer free genetic screening since the 1970s and 80s. Since then, Ostrer has been to schools such as Stanford, Harvard and Yeshiva University.

Genetic testing involves taking a blood sample so that the DNA can be sequenced and analyzed to find out whether a person carries genetic defects or diseases. The students who were tested will get their results back in four to six weeks.

Ostrer says the importance of getting tested as early as possible comes down to having a broader display of options about potential diseases early on. In the past, people learned about their risk for having affected children only after a child was born.

“Through genetic testing, it is possible to identify people whose children may be at increased risk,” says Ostrer.

Ostrer decided to focus his research primarily on Ashkenazi Jews after finding evidence pointing to the reappearance of many prevalent disorders in Jews of Eastern European descent. Diseases such as Canavan disease, cystic fibrosis and Tay-Sachs are some of the most severe. The signs and symptoms of Canavan disease are mental retardation, seizures and cerebral palsy. It progresses rapidly and is fatal by the age of 12, and approximately one in 40 Jews of Eastern European descent is a carrier. Cystic fibrosis causes frequent respiratory infections that later lead to lung damage. The disease also affects the digestive system and ultimately the heart. Approximately one in 20 Ashkenazi Jews are carriers. Tay-Sachs, one of the most feared diseases, causes blindness, mental retardation, seizures and paralysis. It is fatal by age four to five. Approximately one in 25 Eastern European Jews are carriers, while one in 300 are carriers in other groups.

Understanding how the body works is important in understanding Ostrer’s work. We inherit two copies of most genes, one from the mother and one from the father. If one of these genes is mutated, the proteins created from that gene will be abnormal. While a mutation in one copy of a gene can sometimes lead to disease, often a person with one mutation will only be a “carrier” of the disease rather than express the disease themselves. A man and a woman who both carry the genetic defect, however, are at risk for having a child with two defective copies of the gene and thus the disease.

Ostrer’s extensive research on Jewish genetics has created awareness among Jewish college students about what diseases they may be carriers of.

Ostrer tests students, most of whom are unmarried, to give them time to think about their options. Since most college students are not confronting reproductive choices, upon finding out that they are carriers of a gene for a recessive disease, they will be able to make more informed decisions.

Paul Gale ’12, is a little nervous about the results but thinks that testing is important and was surprised that more students were not tested.

“It’s a reality I’d have to face at sometime, and I’d thought I’d get it over with. It puts things into perspective,” says Gale.

Ostrer says that couples in which both partners carry recessive genes for any given disease have two options in order to bear a child.

“For couples who have an affected fetus, there is termination of pregnancy. Another possibility for carrier couples is in vitro fertilization,” says Ostrer. “When you’re in college, it is not too soon to start thinking about it.”

With that in mind, some college students were still skeptical about getting tested.

“There is no need to know now; when and if I decide to have children, I will definitely consider getting screened,” says Nathan Mizrachi ’12.

Students who did choose to get tested were primarily of Ashkenazi descent. However, there is a common misconception that most genetic diseases are prevalent only among Ashkenazi communities.

“There are some conditions that are common in both Ashkenazi and Sephardic communities,” says Ostrer.

For example, cystic fibrosis is present among virtually all Jewish populations, says Ostrer.

Ostrer also says that the there is a very low possibility of there having been any sort of cultural interaction or exchange among Ashkenazi and Sephardic Jews, given that they lived on completely opposite sides of the world.

“Some people think that being a carrier of cystic fibrosis actually increases your resistance to being infected by plague, so there may actually have been natural selection occurring that gave selective survival advantage to people with cystic fibrosis,” says Ostrer, although he says this is only a theory.

Apart from his work on college campuses, Ostrer is also looking to expand these genetic screening tests to involve other ethnic groups. Many ethnic groups have diseases that occur more frequently among their members than in general populations. For example, sickle cell anemia is very common among black populations, and thalassemia is prevalent mainly among individuals of Mediterraean ancestry.

Currently, Ostrer and his team are looking to “develop genetic tests that would be more specific for Iranian and Syrian Jews, which are the third- and second-largest Jewish populations in America.”

Turning back the clock in inherited anaemia

March 18, 2009

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Researchers at Children’s Hospital Boston and Dana-Farber Cancer Institute have identified a way to get red blood cells to produce a form of haemoglobin normally made only before birth or by young infants. This could potentially transform sickle-cell disease and beta-thalassemia – life-threatening inherited anaemia – into benign or nearly benign conditions. The findings were published by the journal Science, in its online Science Express, on December 4.
After birth, babies gradually switch from producing foetal haemoglobin (HbF) to an adult form. From population studies, it’s been known for many years that people who retain the ability to produce HbF have much milder forms of anaemia. Attempts to develop therapies to reactivate HbF directly have been hampered by a lack of understanding of how HbF production is switched off. The drug hydroxyurea often raises HbF in patients, but responses are not uniform and there are potential side effects.

Seeking a better approach, researchers Stuart Orkin, MD, a Howard Hughes Medical Institute investigator at Children’s Hospital Boston, and Vijay Sankaran, an MD-PhD student in Orkin’s lab, in collaboration with researchers at the Broad Institute of Harvard and MIT, capitalised on comprehensive gene association studies that identified DNA sequence variants (altered strings of genetic code) that correlate with HbF levels. In a study published last July, they identified five variants that influence HbF levels and disease severity in a group of 1600 patients with sickle-cell disease, the most common inherited blood disorder in the United States.

The variant with the largest effect on HbF levels contains a gene called BCL11A. Located on chromosome 2, it encodes a transcription factor, a protein that regulates activity of other genes. This turned out to be a valuable lead.

In the new study, led by Orkin and Sankaran, the team showed that BCL11A directly suppresses HbF production. When the researchers suppressed BCL11A itself in human red-blood-cell precursors, the cells began making HbF in large amounts.

“This is one of very few instances in the gene association field where one has been able to take a candidate gene and figure out what it’s doing,” says Orkin, the study’s senior investigator who is also a professor of paediatrics at Harvard Medical School and chair of paediatric oncology at Dana-Farber. “It’s pretty clear that this gene is a silencer of foetal haemoglobin. If you could knock it down to a low level, you could turn on foetal haemoglobin.”

“The discovery of a single gene that profoundly affects foetal haemoglobin levels represents a major breakthrough in the quest for effective therapies for sickle cell disease and thalassemia,” notes Elizabeth G. Nabel, MD, director of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health, which helped support the study. “Researchers can now direct their efforts at developing novel therapies aimed at a specific target that could dramatically alter the course of these often devastating blood disorders. This news should bring great hope to the millions of people worldwide affected by sickle cell disease and thalassemia.”

Increasing levels of HbF would compensate for abnormal or insufficient adult haemoglobin in sickle-cell anaemia or thalassemia, easing symptoms and in some cases achieving a virtual cure, the researchers say. The drug hydroxyurea, used in some patients with haemoglobin disorders, often raises HbF levels, but the increases are modest, it doesn’t work in all patients, it can cause toxicity, and no one knows how it works.

“While it’s been demonstrated that increased levels of HbF ameliorate the severity of sickle cell disease and beta-thalassemia, no direct strategies have yet been developed to increase HbF in these diseases,” says Sankaran. “By reducing BCL11A expression or activity, we may be able to develop targeted therapies.”

Haemoglobin is the protein in red blood cells that carries oxygen to the body’s tissues. In sickle-cell disease, haemoglobin is abnormal, forming long chains that make red blood cells stiff and sickle-shaped. In thalassemia, the body’s ability to produce haemoglobin is severely compromised. The hallmark of both disorders is anaemia that can range from mild to life-threatening. Sickle-cell disease can cause severe pain and eventual organ damage as the abnormal, sickle-shaped cells block blood vessels, robbing tissues of their blood supply; beta-thalassemia requires frequent blood transfusions and then chelation therapy to rid the blood of excess iron that also leads to organ failure.

At birth, HbF comprises between 50 to 95 percent of a child’s haemoglobin before the switch to adult haemoglobin production. The foetal form is thought to be an adaptation to the low oxygen in the foetal environment. Foetal haemoglobin has a higher affinity for oxygen, enabling it to pull oxygen more easily from the mother’s circulation.

Are there potential side effects from boosting foetal haemoglobin levels? No, the researchers say. “Some people with rare genetic deletions have 100 percent foetal haemoglobin, and they’re perfectly normal,” says Orkin.

Orkin and Sankaran are conducting further studies to figure out how the switch from foetal to adult haemoglobin production occurs and how to target BCL11A therapeutically. “Improved understanding will permit the design of therapies for reactivation of HbF in patients with sickle-cell disease or thalassemia,” says Orkin.

(Source: Science: Children’s Hospital Boston: December 2008)

Blood test to detect fetal thalassemia

March 16, 2009

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A study shows maternal blood tests can soon be used to detect certain hereditary diseases such as cystic fibrosis in the unborn fetus.

According to the study published in the Proceedings of the National Academy of Sciences, prenatal diagnosis of cystic fibrosis, thalassemia and sickle cell anemia is possible through a simple blood test performed on mothers.

The study showed that as the fetal DNA circulates in the mother’s blood, a non-invasive blood test can detect these monogenic diseases, caused by a single error in a single gene in the human DNA.

Findings revealed that counting the relative ratio of the mutant genes against normal ones in a simple blood test can detect the presence of monogenic diseases; the accuracy of the method, however, depends on the concentration of fetal DNA in maternal blood.

Currently, invasive procedures such as amniocentesis are used for diagnosing such conditions in the fetus. These procedures pose certain health concerns including miscarriage.

Yale Researchers Find New Way to Fix Faulty Genes Sickle Cell Anemia, Other Inherited Diseases Targeted

March 14, 2009

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( – New Haven, Conn. – Yale University researchers have found a new method to create lasting genetic changes within human cells, opening up the possibility of new treatments for inherited diseases like sickle cell anemia.

The researchers corrected a specific defect within a human gene that causes the blood disorder thalassemia, researchers reported in a study to be published online in the journal Proceedings of the National Academy of Sciences USA. The disease affects production of hemoglobin, the molecule in red blood cells that carries oxygen to the body.

Scientists in the laboratory of Peter Glazer, professor and chair of the Department of Therapeutic Radiology and professor of genetics at the Yale School of Medicine were also able to slip a sort of genetic repair kit into blood stem cells. In theory, repairs to these hematopoietic progenitor cells would enable the body to produce healthy red blood cells indefinitely.

Genetic diseases like thalassemia and sickle cell anemia are particularly problematic to treat because defects are carried within DNA of every cell in the body. Glazer’s laboratory team, headed by Joanna Chin, created a series of artificial DNA molecules designed to bind to specific locations in the genome. These molecules, called triplex-forming oligonucleotides, trigger the DNA’s own repair system, resulting in potentially permanent correction of genetic defects.

In the past, gene-based therapies have met with limited successes in part because of difficulties finding ways to insert a new version of an entire gene into human cells and to have that new gene stay active for a long time. Glazer said their technique avoids some of these pitfalls because it employs oligonucleotides that are short, synthetic DNA molecules that are easier to insert into cells and do not require viruses for their delivery. Importantly, the new technique fixes the defect in the existing gene so it can be expressed in a natural manner, Glazer noted.

Other researchers on the study from Yale contributing to the study were Jean Y. Kuan, Pallavi. S. Lonkar and Diane Krause. Researchers from the National Institute on Aging, University of Kansas, University of Copenhagen in Denmark, and University of North Carolina also were contributing authors. The work was funded by the National Institutes of Health.

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