One can’t squeeze blood from a turnip, but new research suggests that a bit of transgenic tweaking may make it possible to squeeze blood — or at least blood protein — from a grain of rice. In a study published online today in the Proceedings of the National Academy of Sciences, researchers describe rice seeds that can produce substantial quantities of a blood protein called human serum albumin, or HSA1.
HSA is in high demand around the world, both for its role in drug and vaccine production and for use in treating patients with severe burns and other serious conditions such as haemorrhagic shock and liver cirrhosis. The primary source of therapeutic HSA is donated human blood. To overcome limitations caused by blood shortages and contamination of donated blood by viruses, researchers worldwide have been working to create functional HSA either synthetically, with the help of yeast and bacteria, or in transgenic organisms such as cows and tobacco.
In China, which has suffered from HSA shortages and contaminated blood supplies, the idea of using an abundant crop like rice to supplement or even supplant the current albumin supply is an attractive one. “We could ease demand for HSA and reduce the potential risk of spreading viruses in blood plasma. That’s what prompted me to do something like this,” says Daichang Yang, a plant biotechnologist at Wuhan University, China, who led the research.
Part of the difficulty in producing synthetic or laboratory versions of HSA, however, has been developing a system with a high yield, low cost and low risk of immune reaction. Yang thinks that his seed-based method has the potential to satisfy all of those requirements. “Scientists have been using plants to produce HSA for two decades, but the yield is too low,” he says. But seeds have evolved to be specialized for protein storage, providing the optimal bioreactor for HSA production. “The higher yield could allow for lower costs,” he says.
Yang and his colleagues inserted the gene encoding HSA into their rice plants in such a way that the gene was activated during seed production, and the resulting protein was stored in the rice grain along with nutrients normally used to help nurture a germinating embryo. The final product was a crop of rice seeds in which HSA made up more than 10% of the seeds’ total soluble protein — one of the best yields of recombinant protein from plants to date.
It was relatively simple for Yang to extract HSA from the grains. Because the rice genome was completed in 2005, he was able to use this information to separate the human protein from those of rice.
The rice-derived protein was shown to be functionally equivalent to the version found in human blood plasma. Not only were the two chemically and physically identical, but they were also similar when tested for medical efficacy and immune reactivity. In rats with liver disease, both types of HSA proved equally effective in relieving symptoms associated with cirrhosis. And rats that were given rice-derived HSA showed no stronger immune reaction than animals that had been given the plasma-derived version.
“This recombinant method has a good shot at making HSA more abundantly and more safely than human plasma, and it will at least have a shot at being as cost-effective,” says William Velander, an expert in genetically engineered therapeutics at the University of Nebraska–Lincoln.
Don Brooks, who develops synthetic biocompatible materials at the University of British Columbia in Vancouver, Canada, and who has created his own synthetic version of the HSA protein, agrees. “I’m convinced that what they’ve produced is a good reproduction of the human material,” he says. “The lab work they’ve done is pretty impressive. They still have to do it in people to be sure it’s as safe as native material, but it’s looking pretty good.”
Yang aims to move into human testing next. He has submitted his first clinical-trial application to the US Food and Drug Administration, and hopes to begin testing the rice-derived HSA in humans within the next two years.
- He, Y. et al. Proc. Natl Acad. Sci. advance online publication http://dx.doi.org/10.1073/pnas.1109736108 (2011).
Two of the largest studies yet carried out on the genetics of schizophrenia in Chinese populations have turned up three genetic loci, or chromosomal regions, previously not known to be related to the disease.
These genome-wide association studies (GWAS), done independently and published in Nature Genetics on 30 October1,2, also begin to redress a geographical imbalance: until now, GWAS have focused mainly on Western populations.
Roughly 1 in 100 people will suffer from schizophrenia in their lifetimes, which is considered largely heritable (up to 80%). But this genetic influence seems to be produced by hundreds of variations in DNA, each of which increases risk by a small amount. Researchers have so far found some 20 such variants, but have been unable to pin down the exact genes that are affected by those variations or molecular mechanisms that cause the disease.
In one study1, a group led by Wei Huang, a geneticist at the Chinese National Human Genome Centre in Shanghai, and Dai Zhang a neuroscientist at Peking University in Beijing, compared the genomes of 746 people with schizophrenia with those of 1,599 controls. They found that previously unknown variations in a region of chromosome 11 — 11p11.2 — were linked with the disease. The correlation was verified in follow-up studies of another 4,027 people with schizophrenia and 5,603 controls.
In another study2, a team led by Lin He and Yongyong Shi, of the Bio-X Institutes at Shanghai Jiao Tong University, compared the genomes of 3,750 people with schizophrenia with those of 6,468 controls. They turned up two culprit regions: 8p12 and 1q24.2. The association with schizophrenia of the two regions was validated in another study of 4,383 people with schizophrenia and 4,539 controls.
“[These genetic loci] represent new potential targets to help understand schizophrenia. As we have only a relatively small number, this represents an important increase,” says Pamela Sklar, chief of psychiatric genomics at the Mount Sinai School of Medicine in New York, who was not involved in either study.
Something old, something new
Both studies also reinforce previous findings in studies of European populations3,4,5 that a region of chromosome 6 associated with the major histocompatibility complex (MHC), a gene family involved in the immune system and autoimmunity, is involved in schizophrenia.
“This definitely strengthens the case that one or more genetic factors in this broad region are involved in disease risk,” says Shaun Purcell, who develops statistical and computational tools for genetic studies at Massachusetts General Hospital in Boston.
Pablo Gejman, a psychiatry researcher at the University of Chicago’s Pritzker School of Medicine, agrees. “The replication of the MHC locus is of great potential significance,” he says. “The MHC is a well replicated common variant locus for schizophrenia and suggests aetiological mechanisms of disease that have not been previously considered with sufficient focus.”
But there is much work still to be done. “None of the studies by themselves pinpoint specific genes or causal alleles in this large, complex [MHC] region,” says Purcell. The next step might be to integrate the Chinese and European data, he adds. “It would be great to see these large data sets combined.”
Grist for the mill
The three newly implicated loci will point to future studies, but researchers will have to start nailing down the genes and specific molecular mechanisms that drive the disease. “The connections with underlying gene expression will need deeper exploration to verify the connection with schizophrenia pathogenesis,” says Sklar.
Lin He says the next step is to identify the risk genes affected by the variants in the interesting regions. “After carrying out fine mapping studies and functional validations, we might have the chance to report the right risk gene in an associated region soon,” he says.
It is still unclear whether the genetics at work in schizophrenia differ between Asian- and European-descended populations, although the latest studies may be a first step towards uncovering the answer. “These are the first large GWAS studies in Asians,” says Sklar, adding that “the extent to which population-specific genetic factors exist is an important and open question”.
“This is a largely understudied topic,” says Gejman. “GWAS studies are potentially helpful, but the studied samples will need to be much larger to understand the genetic architecture of schizophrenia in the Chinese population, as well as in European populations.”
- Yue, W.–H. et al. Nature Genet. http://dx.doi.org/10.1038/ng.979 (2011).
- Shi, Y. et al. Nature Genet. http://dx.doi.org/10.1038/ng.980 (2011).
- Stefansson, H. et al. Nature 460, 744-747 (2009). | Article | PubMed | ISI | ChemPort |
- The International Schizophrenia Consortium Nature 460, 748-752 (2009). | Article | PubMed |
- Shi, J. et al. Nature 460, 753-757 (2009). | Article | PubMed | ISI | ChemPort |