Genetic Medicines

I attended a conference entitled ‘Personalized Medicine: Concepts, Promises, Successes and Challenges,‘ organized by the Jacques Loeb Center for the History and Philosophy of the Life Sciences and the National Inst. for Biotechnology in the Negev (NIBN) at the Ben Gurion University in Beer Sheva, where I am a Visiting Professor of Chemistry.  What I was disappointed to discover was that most of the speakers pointed out the difficulties and problems, both medical and ethical, of ever reaching a truly successful personalized approach to medicine,

This is especially true of such diseases as cancer that are now known to be genetically complex, and in which a series of genes are turned on and turned off compared to the “normal,” so that it is virtually impossible to overcome this genetic heterogeneity.  A great deal of work is being done to characterize this heterogeneity, but unfortunately there has been little success in overcoming this problem.  One of the reasons for this is  that the medicines being developed against cancer and other diseases are small molecules that selectively inhibit specific proteins that are produced in aberrantly functioning cells such as metastatic cells.   It is impossible to achieve any level of inhibition of a series of such proteins with small molecule drugs that are not selective enough.

If I say I have a possible solution to this problem, very few people will believe me, but the fact is that cancer and like disorders are genetic diseases, that involve the malfunction of at least several genes (due to serial mutations).  In order to cure a genetic disease I maintain that it is necessary to use a genetic approach to therapy, in other words to develop genetic medicines.  I used this title for an article I published in Scientific American in 1994 (Cohen, JS, and Hogan, M. The new genetic medicines, Scientific American271 (6): 50-55, 1994.).

What are genetic medicines? They are molecules that have a base sequence that can bind selectively to a specific target sequence in the messenger RNA of a gene that is carcinogenic, that is causing aberrant cell behavior, i.e. cancer.  Note that it is rarely possible to bind a complementary sequence to DNA, that is covered in proteins and carefully protected, since it contains the genetic information.  But, as originally predicted by Francois Jacob and Jacques Monod, and subsequently proven by Jacob, Brenner and Meselson in 1961 at Cal. Tech., there are messenger molecules that are RNA (mRNA) that take the sequence of DNA (called the sense sequence) from the gene out into the cell, where they are expressed as protein via the protein biosynthesis mechanism involving the ribosome.  Naturally, the complementary sequence is called the antisense sequence, and this is the name give to the approach of using chemically modified analogs of DNA as drugs to inhibit gene expression via the interaction with mRNA.

Now it is true that this antisense approach has serious problems, for example, (1) Stability. It is necessary to design and synthesize chemically modified analogs of DNA to ensure that they are stable in the cell, protected from the prevalent enzymes that degrade foreign DNA, known as nucleases.  For example, we pioneered the use of analogs with a single substitution of a sulfur atom in place of an oxygen on the phosphate group of DNA (eight such PS (thio-phosphate) analogs have been approved by the FDA for human use); (2)  Uptake. It us very difficult to get such large molecules into the cell where they are required to function.  But this can be overcome by designing the analogs to be more hydrophobic than normal DNA, or using liposomes to deliver them to the cells (we carried out studies on liposome delivery of antisense oligos, in collaboration with Yehezkel Barenholz at Hebrew University, some years ago); (3) Cost. The cost of such specialized molecules is high, but if they work they would save even more money from futile treatments with small molecule drugs that eventually fail; (4) Biological therapy. There is a trend to use biological approaches to therapy, but these tend to be complex and not easily controllable, so that approaches using gene therapy and what is known as siRNA, naturally occurring gene silencing RNA’s, have not so far been successful; (5)  The molecules are complex and in some cases form sequence dependent structures that reduce their efficacy.

However, my contention is that we must work hard to overcome these difficulties in order to take advantage of the truly great potential of genetic medicines.  This approach  has the potential to overcome the very genetic heterogeneity oi cancer that has prevented current progress by using a  cocktail of DNA analogs with selected base sequences that could be the basis for a truly personalized therapy.