1. Synthetic biology in medicine: genetics as a target

“The genome is now a treatment goal,” summed up Prashant Mali, a professor at the University of California, San Diego. This is in large part due to CRISPR, the new gene-editing technique that allows scientists to modify DNA (or RNA), which is much easier and more versatile than previous techniques. This makes it a great tool for lab research, but also for designing therapies.

CRISPR is one of the great hopes for treating genetic diseases caused by only one gene (monogenic disorders) or even for others with many genes involved, but there are still many limitations that must be taken into account. For example, sometimes the tool cuts the DNA in the wrong place (off-target effects) and the cell’s own repair mechanisms aren’t totally under control yet, so there can be unintended mutations in the place of action (on-target effects). It can even trigger immune reactions, when the organism considers it a foreign body. Mali’s group is searching for safer alternatives, for example with enzymes that cut RNA, which conveys information from DNA, that wouldn’t cause the body to reject them.

Another complication with CRISPR is getting the tool to enough of the cells that should be modified. This line is the focus of the group led by Matthew Porteus, professor of Pediatrics at Stanford. They have developed a method that combines two elements: on one hand, they put in the protein that makes the cut with the RNA to guide it as ribonucleoproteins. On the other, using a specific type of virus, they transport the DNA molds to encourage correct repair. The method seems more efficient and to have fewer problems with rejection. It has already been tested in diseases like sickle-cell anemia and it seems to be advancing through incipient clinical trials.

Porteus is hopeful about the possibilities this tool has to offer, but is also concerned about some of the issues that come along with it.  Both ethical, in some cases, and in terms of safety and equality. If applied to embryos, he advocates for “a functional moratorium” while research advances, and that it be used to achieve “healthier children, not designer children.” Regarding therapies in adults, he believes “it would be a success even if we only cure one patient with sickle-cell anemia, but how can we have a global impact if many places don’t have specialized hospitals to develop it?”

Another illness researchers hope to begin clinical trials on soon is hemolytic anemia due to pyruvate kinase deficiency, a disorder caused by a mutation of just one gene that can be very serious as it causes mass destruction of red blood cells. The group led by José Carlos Segovia, division head at Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas en Madrid (CIEMAT), submitted a trial proposal to the US FDA and the Spanish Agency of Medicines and Medical Products and expects to begin the trial in the coming months.  It is based on inserting the right gene using a special type of virus, but they are also working on doing so with the technique developed by Porteus’ team, combining ribonucleoproteins and viruses that don’t become part of the genome.

Beyond gene therapy as such, which corrects DNA permanently, there are new forms of cancer immunotherapy, called CAR-T. They consist in extracting defense cells from the patient, modifying them in the lab and putting them back into the patient’s blood to attack the tumor. The modification tends to be a work of ‘engineering’ to add an ‘artificial’ receptor that is particularly powerful and specific, generally targeting a specific type of cells in the immune system. This is why it is being used already for certain types of leukemia and lymphoma, and there are more than 200 clinical trials currently underway. One of them is being done at Hospital Clinic Barcelona and “involves over 150 professionals,” explains Manel Juan, head of the Immunology section at the Hospital and one of the trial leaders.

Another way to fight cancer is being studied in the group led by Luis Ángel Fernández, principal investigator at the Spanish National Center for Biotechnology in Madrid (CNB-CSIC). It consists in modifying bacteria so they specifically target tumors and can fight them. They are doing this with a harmless variety of Escherichia coli with information added so they produce adhesins, specific proteins that take them to the tumor. Information has even been added so they will produce injectosomes, filaments that act like molecular syringes and are normally found in dangerous varieties. In this case, the aim is to inject therapeutic molecules into tumor cells.

Bacteria are really one of the most attractive fields of synthetic biology, and with the most potential, with applications in medicine and beyond.