Editing Human Stem Cell Genes Could Let Patients Grow Their Own Cures

By Rebecca Boyle

Human Genome Sequence Editing the arrangement of a sequence of these letters corrected a genetic mutation in stem cells, a breakthrough combination of stem cell therapy and genetic modification.Wikimedia Commons

For the first time, scientists using a combination of gene-editing technologies have corrected mutations in a patient’s own induced stem cells. The breakthrough could pave the way towardreprogramming a person’s own cells to cure genetic diseases, rather than using transplanted organs and drug therapies.

Researchers led by two institutions in the UK corrected a mutation in cells derived from a patient with a metabolic liver disease.

Stem cells — embryonic ones and induced pluripotent ones — can turn into any type of cell, so they hold promise for treating a host of disorders. They can come with unwanted mutations, however. For one thing, induced pluripotent stem cells (iPS cells) would contain the same genetic defects as the rest of a patient’s body, so you’d have to remove those defects before you could treat a person with his or her own cells. But this removal can be imprecise; current editing methods can cause misplaced alleles or residual genetic sequences, which can lead to formation of cancer or other unwanted side effects. And recent breakthroughs in gene editing methods have not involved stem cells.

To work on stem cells, you would need a very careful editing method to snip out incorrect gene sequences in the stem cells and replace them with the correct kind. And that’s what these researchers have done.

Scientists at the Wellcome Trust Sanger Institute and the University of Cambridge worked with a mutation in a gene responsible for coding a specific protein in the liver. It’s a common mutation, found in about 1 of every 2,000 people of European descent, and it’s also a fairly simple mutation, with just one transposition of letters.

The team took skin cells from a patient and turned them into iPS cells. Then they used genetic scissors, zinc-finger nucleases, to snip the genetic sequence at the site of the mutation. They also used a piggyBAC transposon, which cuts and pastes genetic information. In this way, they were able to correct both alleles involved in the mutation of this liver gene.

Once the stem cells were corrected, the team induced them to become liver cells. These were transplanted in mice with the liver disorder. The cells restored the liver’s proper function, and were still working properly after six weeks, the researchers said.

This was an incredibly difficult maneuver, and it’s the first time anyone has been able to pull it off, the researchers say. Researcher David Lomas told the BBC it was “ridiculously hard.”

But it’s proof, at least in principle, that well-edited genetic sequences in induced human stem cells can provide new cells for a variety of clinical treatments. The paper was published in today’s issue of Nature.

[via BBC]

Growing Schizophrenic Brain Cells In A Dish Helps Neuroscientists Study Mental Illness Up Close

By Rebecca Boyle

Skin Cell-Derived Neurons Human neurons differentiated from skin-derived stem cells. Ji-Eun Kim and Anirvan Ghosh, UCSD/via Kavli Foundation

Studying mental illnesses involves complex brain-monitoring technology to watch how neurons and large-scale brain components are functioning or malfunctioning. But researchers are increasingly getting out of their patients’ heads, monitoring brain cells in petri dishes instead. This is possible with stem cells, and it could yield plenty of new avenues for psychiatric research.

Researchers at the Salk Institute for Biological Studies and the Kavli Institute for Brain and Mind in San Diego are using skin cells from patients with schizophrenia, autism and other disorders, and producing induced pluripotent stem cells. These cells are then induced to become neurons, which are grown in a lab so the neuroscientists can monitor the cells’ development or test potential new drugs.

Initial studies using this method show that the neurons of schizophrenics look similar to normal neurons, but they have different synaptic connections. And it appears that some psychiatric drugs cause physical changes in neurons, an unexpected finding.

Neuroscientists Fred (Rusty) Gage and Anirvan Ghosh are both working on “disease in a dish” research, hoping to unveil the genetic basis underlying various mental illnesses. They describe their work in an interview with the Kavli Foundation, which supports their work; go here to read a transcript of the interview.

For now, the research has left the neurons to form connections unimpeded — they have not been induced to become specific neuronal subtypes, like dopamine neurons or cortical neurons. But future work will attempt to form those specific types so that their interactions can be studied — for instance, how dopamine neurons interface with the substantia nigra region of the brain, which affects balance and movement and is related to the development of Parkinson’s disease. Gage said that type of work would require some other technological advances, perhaps microfluidic chambers that will isolate different neurons from each other and regulate how their synapses form.

Without the stem cells in a petri dish, monitoring how human neurons grow and connect would otherwise be impossible, the researchers say. And understanding that development can go a long way toward treating mental disorders — not to mention understanding the physiological connections that define what it means to be human.

[Kavli Foundation]

Time to Invest in Africa and Africa’s Capital Markets, World Bank Vice President Says

The World Bank’s Vice President for Africa Obiageli Ezekwesili called Thursday from the London Stock Exchange for investors worldwide to invest in Africa and its budding capital markets. “Africa has taught the world a lesson in macroeconomic reform and stability,” Ezekwesili told the audience at an African Investment Summit hosted at the Stock Exchange. She urged investors who are in search of the right market at a time of growing fears of a global recession to “rediscover Africa”. “Africa’s fundamentals appear strong, and the continent’s outlook remains positive,” Ezekwesili said, pointing to the continent’s rapid rebound from the 2008-2009 global financial crisis, and its higher GDP growth rates projected to be 4.8 percent, 5.2 percent and 5.5 percent respectively in 2011, 2012 and 2013. It makes business sense to bet on Africa’s capital markets, she said, at a time when “global equity markets are headed for their worst quarter since 2008”, and returns on investments in Africa are among some of the best in the world. Ezekwesili cited a recent study by Oxford University Professor, Paul Collier, which found the return on capital for over 950 African enterprises to be on the average 11 percent higher than in Latin America and Asia, and 70 percent more profitable if compared against similar Chinese firms. Capital is flowing to Africa, the World Bank vice president explained, “because the continent has become a friendlier and more profitable market, about which businesses, consumers, investors and development partners are all bullish. Investors who joined the flight for quality at the onset of the 2008-2009 global crisis can now testify, Ezekwesili argued, that “Africa stayed stable” even as the global stock exchanges went on a wild roller coaster ride. Recovery on African stock markets came fast even though their limited liquidity and relative small size was amplified. While initial hopes that investors–weary of markets in developed countries–would seek opportunities in Africa and other developing regions were misplaced, most African stock markets with the exception of the Johannesburg Stock Exchange have grown robustly, doubling their market capitalisation between 1992 and 2002, from $113.4 billion to $244.7 billion. In a move that is likely to set a new record, the Lagos Stock Exchange, the region’s fastest-growing market, plans to increase its current capitalization from $40 billion to $1 trillion in five years. According to Ezekwesili, “one of the key lessons of the past global crisis is that Africa knows how to shrug off the impact”. “Been there, done that”, was the attitude she said African finance ministers who attended the September 23-24 Annual Meetings of the World Bank and International Monetary Fund  in Washington, DC, had on being told that news of a potential global crisis meant even more reforms on their part. Policy reforms lead to positive growth One explanation for Africa’s success is the region’s sustained pace of meaningful reforms. As many as 36 of the 46 African countries surveyed by the Doing Business report have implemented major reforms over the last five years, including those whose ranking has slipped or has not improved. Ezekwesili said the continent of which she speaks is “an exciting, new Africa… on the cusp of an economic revolution similar to China’s and India’s”. She described it as a region of abundant opportunities in agriculture, agribusiness and agro-processing; with strong demand for capital in infrastructure development; but also a region in need of a second round of investments to upgrade the ICT sector, expand broadband use, mobile banking and Internet access. Ezekwesili called on investors to help themselves, by not focusing too narrowly on making the fast buck, but on building social accountability and transparency and fostering the fight against corruption, promoting social corporate responsibility by helping to develop the human capital and labor skills that will be needed if the “new Africa” is to lure some of the 85-to-90 million labor-intensive jobs in light manufacturing that wage pressures will force firms in China to off-shore in the next three-to-five years. Africa, Ezekwesili said, needs to replicate the knowledge that enabled policy reforms to precede efficient public investments before private capital helped turn a loss-making sector such as telecommunications into the ICT revolution the continent has witnessed. Strengthening Africa’s capital markets whose success is intrinsically linked to the economic success of the continent is essential if Africa is to fulfill its vast potential, said Bill Mills, CEO of Europe, Middle East, and Africa at Citigroup, one of the co-sponsors of the summit. Ezekwesili pledged World Bank support to continue to help African governments embrace the right reforms, build the right institutions, make the right public investments, build the resilience of their economies to shocks and make the right policy choices, including diversifying their economies, developing the private sector and protecting the poor and most vulnerable in a time of crisis.  Admitting that “nobody really knows for certain the extent of the effects of the crisis on the most fragile, debt-ridden and budget-strapped economies,” Ezekwesili said even when a global crisis hits Africa some of the most effective mitigating effects would come from leaders not taking their hands off the reins of reforms but also from stronger growth in countries like South Africa and Nigeria, as well as from a return to growth after violent conflicts such as in Cote d’Ivoire.