Nature Biotechnology 25, 1219 - 1220 (2007)

Undersupported, but undaunted

Undersupported, but undaunted

Henry Daniell says that having a cover photo in two high-impact journals raised the visibility of chloroplast engineering technology.

Henry Daniell is not easily discouraged. After all, his invention—a universal chloroplast vector, which he first reported on in our pages in 1998 (ref. 1)—is now patented in 15 countries, thanks in no small measure, he thinks, to the validation it received by surviving the review process. What's not so good for Daniell and everyone else trying to commercialize a product from transgenic plants is the enormous cost of bringing such a product to market, especially considering the difficulty of obtaining the necessary capital.

But on the surface, things are going well. Recent work from his laboratory and elsewhere has demonstrated that human proteins like insulin and interferon can be made in plants with engineered chloroplasts at levels not possible with nuclear trangenes. In a later Nature Biotechnology paper2, he reported that 45% of tobacco leaf protein was derived from a transgene, the insecticidal protein cry2Aa2, representing the highest level of foreign gene expression ever reported in plants at the time. Since then, equally impressive levels of insulin and interferon have been achieved using the system3, 4. Low expression levels is the thing that Daniell feels has held back the field of plant-made pharmaceuticals—or at least one of the things. And with his chloroplast vector, which inserts into all 10,000 copies of the chloroplast genome, he feels he has that problem solved.

Another virtue of targeting the chloroplast genome with a transgene is that containment is not an issue. Because the chloroplast genome is maternally inherited, pollen won't disseminate the transgene. And with tobacco, one of the Daniell systems, at the time of harvest, there are no flowers (they harvest leaves), so no reproductive organs are involved, which should make regulators breathe a sigh of relief. In fact, four transgenic plants have been approved for field trials, and the results of one such trial (insulin) have recently been reported5.

Daniell thinks he can further improve the odds of success with plants by delivering the expressed protein in plant powder. He recently showed that oral delivery of powdered plant cells expressing human proinsulin protected non-obese diabetic mice against development of insulitis. This could be a boon to manufacturing because it would eliminate costly fermentation and purification, associated with other biomanufacturing technologies.

Daniell is the technology founder of two companies; Chlorogen, (St. Louis) which has invested $15 million to develop a proprietary protein therapeutic and Gencrest (Raritan, NJ, USA), which is investing $20 million in phase 1 to advance four chloroplast-derived therapeutics from the Daniell laboratory that have been shown to be functional in animal studies. In keeping with Daniell's personal interest in solving problems in the developing world—he was born in India—GenCrest is working on chloroplast-derived vaccines.


All this sounds good. But with only $20 million in the bank, Daniell knows it's not going to be enough to take any biopharmaceutical product through clinical trials. So even with the imprimatur of venture capitalists, he's still a long way from where he needs to be. But Daniell goes on undeterred—moving antigens for cholera, malaria, amebiasis, rotavirus and tuberculosis into plants, and hoping for the day that these will all make their way to the people who most need them.



  1. Daniell, H. et al. Containment of herbicide resistance through genetic engineering of the chloroplast genome. Nat. Biotechnol. 16, 345–348 (1998). (154 citations) | Article | PubMed | ISI | ChemPort |
  2. De Cosa, B. et al. Overexpression of the Bt cry2Aa2 operon in chloroplasts leads to formation of insecticidal crystals. Nat. Biotechnol. 19, 71–74 (2001). (125 citations) | Article | PubMed | ISI | ChemPort |
  3. Ruhlman, T. et al. Expression of cholera-toxin B–proinsulin fusion protein in lettuce and tobacco chloroplasts—oral administration protects against development of insulitis in non-obese diabetic mice. Plant Biotechnol. J. 5, 495–510 (2007). | Article | PubMed | ChemPort |
  4. Arlen, P.A. et al. Field production and functional evalu-ation of chloroplast-derived interferon-alpha2b. Plant Biotechnol. J. 5, 511–525 (2007). | Article | PubMed | ChemPort |
  5. Daniell, H. Transgene containment by maternal inheritance: effective or elusive? Proc. Natl. Acad. Sci. USA 104, 6879–6880 (2007). | Article | PubMed | ChemPort |