heart disease

The Wellcome Trust Sanger Institute today published a press release presenting the discovery of a gene mutation in roughly 1% of the world population that virtually guarantees the onset of heart disease in its carriers.  Heart disease is the leading cause of death in the United States and in many other developed nations.  Nearly 700,000 Americans die every year from heart disease, accounting for nearly 1 in 3 U.S. deaths (1).

The mutation, a deletion of 25 letters of genetic code from the heart protein gene MYBPC3, is virtually restricted to people from the Indian subcontinent.  Roughly 4% of those with a genetic lineage from the Indian subcontinent carry the mutation, which equates to about 60 Million people, or 1% of world population.

The discovery of this gene is just the tip of the iceberg of what is to come in a new era of cheap and fast genetic analysis.  Armed with the exact gene and therefore the exact mechanism by which 60 million people are destined to acquire heart disease, we can now work on therapies for saving them.

From the press release:

Scientists express this genetic risk as an odds ratio, where 1.2 would be a small effect and 2.0 a large one. For the MYBPC3 mutation, the odds ratio is almost off-scale, a staggering 7.0. Carriers usually show few symptoms until middle age, but after that age most are symptomatic and suffer from a range of effects, at worst sudden cardiac death.

“The mutation leads to the formation of an abnormal protein,” explained the study leader, Kumarasamy Thangaraj from the Centre for Cellular and Molecular Biology, Hyderabad, India. “Young people can degrade the abnormal protein and remain healthy, but as they get older it builds up and eventually results in the symptoms we see.”

This sensational claim is misleading since the practice of genetically screening embryos, as was done in this case, has been commonplace for over a decade now.  Such screening, called PGD,  is almost exclusively used to look for debilitating characteristics in the embryo, such as cystic fibrosis.  What is unique about this particular baby is that the embryo was screened not for a true debilitating disease, but rather for a gene that could potentially be harmful later in the child’s life.  The gene, called BRCA1, increases the risk of breast cancer in females by as much as seven times.

This genetically screened baby represents a decisive step down the slippery slope of screening embryos not only for genetic defects that are seriously debilitating, but also for genetic traits that are simply risky or undesirable.  Future “parents to be” in the UK and elsewhere may use this as a precedent to support the screening of all sorts of other traits.  Screening for genes that are completely unrelated to disease, such as height or intelligence, is therefore a step closer to reality.  Selection of the sex of an embryo has long been a widespread practice, serving as another precedent for more relaxed limitations on embryo screening.

For those that want to know more about the field of pre-screening embryos a detailed explanation follows:

Genetic pre-screening of embryos before implantation into the uterus is known in the industry as preimplantation genetic diagnosis, or PGD.  Two excellent sources of information about PGD are a wikipedia article and the center for preimplantation genetics, both of which were referenced heavily for this report.

PGD can only be performed on embryos in vitro (in a laboratory). That means the test is always performed in conjunction with an in vitro fertilization cycle.   The steps are as follows:

1. Fertility drugs are given to the mother to stimulate the development of multiple eggs in her ovaries

2.  Eggs are retrieved from the ovaries using an ultrasound guided needle.

3.  Eggs are then mixed with the partner’s sperm in the IVF Laboratory and placed in the incubator for fertilization and embryo growth to the 4 – 12 cell stage.

4.  At this point, one or two cells will be biopsied (removed) from the embryo(s)

5.  PGD will be performed, which means the biopsied cells will be analyzed for genetic and chromosomal defects/traits.

5.  Embryos whose biopsied cells were shown to have an undesirable trait will be terminated.  The remaining “good” embryos are candidates that can be implanted into the mother’s uterus for development into a fetus.

Directly from the Center for Preimplantation Genetics:

Misdiagnosis
Misdiagnosis can occur due to mosaicism within the embryo. Some embryos may contain blastomeres (cells produced by the cleavage [division] of a fertilized egg) which are genetically normal and, within the same embryo, other blastomeres which are abnormal. This is called mosaicism. For this reason, a diagnosis may be incorrect. This may result in the transfer of an embryo carrying a chromosome abnormality or the failure to transfer a normal embryo.

Experimental error can also account for a misdiagnosis. Improper cell fixation techniques, DNA denaturation errors, allelic drop-out or amplification of contaminated DNA can lead to a wrong diagnosis.

A recent report of the European Society of Human Reproduction and Embryology (ESHRE) documented the PGD results from 25 consortium members from 1999 to 2001. There were 8 confirmed misdiagnoses from 451 PGD tested embryos; 1% (3/305) for chromosome analyses and 3.4% (5/146) for single gene disorders.

Are there risks associated with PGD?
The micromanipulation techniques used for blastomere biopsy are safe with little risk to the embryo. The risk of accidental damage to the embryo during biopsy is less than 1%. There is no risk to the embryo following chromosomal or single gene defect analysis because the analyzed cells are not put back into the embryo. There may be a slightly lower likelihood of implantation after embryo biopsy compared to an embryo not having been biopsied. Other risks may become apparent over time, but to date appear quite limited and need to be weighed against the potential benefits for each couple.

image: cell being removed from embryo (source)

The patients in the study suffer from Leber’s congenital amaurosis (LCA), a rare inherited eye disease caused by a defective gene called RPE65. The condition appears at birth or in the first few months of life and causes progressive deterioration in vision.  Until now there have been no effective treatments available.

Below is an excellent “must watch” video from CBS documenting this amazing breakthrough, followed by further details and comments:

Normally, cells in the eye activate the RPE65 gene to produce an enzyme necessary for the function and health of a protective layer of cells underlying light- and color-detecting photoreceptor cells in the eye.  Patients with a defective RPE65 gene are unable to produce this enzyme, leading to photoreceptor cells that are otherwise healthy but unable to do their job.  Over many years the photoreceptor cells themselves steadily become damaged beyond repair.

Researchers theorized that if they could “upgrade” these photoreceptor cells with the non-defective gene then damage to the photoreceptor cells would cease and any remaining healthy cells would regain their ability to function.  A virus was used to inject the functioning gene into the target cells and within a week vision improved and remained so after 90 days — the study’s endpoint.

In theory, the younger the patient, the better this therapy will work because the degenerative nature of the disease will have had less time to cause permanent destruction to photoreceptor cells.  Trials are now underway with younger patients and the researchers are hopeful that these younger patients will see substantial, perhaps even full recovery of vision.

Wired has an excellent review of this story.  A few excerpts:

Though the trial was designed to test the therapy’s safety rather than its efficacy, its benefits were so impressive that the researchers decided to publicize their results.

“One of the patients said that the dim red light from his alarm clock had gotten so bright that it bothered him,” said Artur Cideciyan, a University of Pennsylvania opthamologist and co-author of the study. “He had to turn away from it while he was sleeping.”

Cideciyan’s study, published today in the Proceedings of the National Academy of Sciences, is one of three simultaneous trials of gene therapy for Leber’s Congenital Amaurosis, also known as LCA. Results from the first two were published in April in the New England Journal of Medicine:

Much more detail can be gathered at the following links:

http://www.ucl.ac.uk/ioo/research/patients/clinical_trials.html

http://www.ucl.ac.uk/ioo/research/patients/clinical_trials_furtherinfo.html

http://www.pnas.org/content/102/17/6177.full.pdf