Like many individual investors, I have kept an eye on the emerging field of regenerative medicine for several years now. And why not? The potential to replace defective organs, cure incurable diseases, regenerate fingers, teeth & penises and grow a steak in a petri dish are truly awe-inspiring. Science fiction is becoming reality. A select group of pioneers will undoubtedly earn Nobel Prizes.
The impact of these technologies will be transformative. A simple web search reveals numerous articles and presentations extolling world-changing potential benefits such as the end of aging, slowing global warming, the end of diseases, the end of poverty and malnutrition and the end of organ transplantations. Heady stuff.
I cringe, however, when I read such puffery because it encourages unrealistic expectations from non-insiders. Regenerative medicine is not a magic bullet and it will not cure all of our ills in the medium or long term. Regenerative medicine is a continuum. It represents incremental steps in cell, tissue, organ and biologic systems research that began many decades ago. Progress has been steady but slow. Progress will continue to be steady but slow. The reasons for this are many. For example, the technical challenges and complexity of regenerative medicine are literally off the charts. I am amazed that researchers have gotten as far as they have. When ethical and safety issues are added to the mix, it is clear to see why prudence has and will continue to be the best prescription.
A tragic example of the risk of moving too quickly occurred in 1999 at the University of Pennsylvania. Jesse Gelsinger, an 18-year old patient who was a mild sufferer of the genetic disease, ornithine transcarbamylase deficiency, was recruited for a clinical trial for a treatment for infants born with severe OTD (usually fatal at birth). Mr. Gelsinger was able to survive on medication and a restricted diet, so he should have been excluded from the trial. Nevertheless, clinical investigators recruited him anyway. Doctors injected him with an adenoviral vector carrying a corrected gene to test the safety of the procedure. He had a massive immune response to the vector that led to organ failure and death four days later. The co-lead investigator was subsequently found to have violated several rules of conduct in the case.
The reverberations of this unfortunate episode are still being felt in regenerative medicine. This is one reason why Phase I clinical trials will take an inordinate amount of time. Investigators and regulators are being extraordinarily cautious in order to avoid another serious adverse event (SAE), heaven forbid, death. Some Phase I patients, for example, have been followed for as long as 18 months post dosing before concluding it was safe. This is extraordinary for a safety trial. Another SAE is the most significant near-term risk, in my opinion, to the current pace of progress.
Since the market is currently keeping its distance from most regenerative medicine firms and the hype machine is relatively quiet, now is as good a time as any to review the space. This is a basic review by a nonprofessional for lay investors, so all of you MD/PhD's out there need to adjust your expectations accordingly. I do not intend for this information to be course material for graduate students.
The term "regenerative medicine" is attributed to Bill Haseltine, founder of Human Genome Sciences. The term first appeared in print in 1992 in an article by Leland Kaiser. There are three main components of regenerative medicine that I address in this article: Gene Therapy, Cell Therapy and Tissue Engineering. The last area contains two subgroups that have generated press attention, 3D Bioprinting and In Vitro Meat. I will review these as well. The basic graphic below depicts my approach:
For those of you who desire a more eloquent depiction of the field of regenerative medicine, here is the FDA's perspective:
1. Replacing a mutated gene that causes diseases with a healthy copy of the gene.
2. Inactivating a mutant gene that is functioning improperly.
3. Introducing a new gene into the body to fight disease.
Gene therapy offers the first real hope for sufferers of a long list of genetic diseases like cystic fibrosis, multiple sclerosis, sickle cell anemia and muscular dystrophy.
Progress has been slow, however, due to the enormous technical challenges of carrying large segments of DNA and delivering them to the correct location on the genome. Utilizing a viral vector has been the most common method for getting DNA into the cells because of the way viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. Retroviruses, adenoviruses and adeno-associated viruses are the most common. Liposomes have also been used as an alternative approach.
Figuring out how to get the DNA into the cells is the most significant hurdle in the field. In the 23 years since the first patient received gene therapy in 1990, not one product has made it through the U.S. regulatory approval process. The technical hurdles have been methodically surmounted, though, and optimism has grown that FDA clearance will finally occur sometime in the next couple of years. The EMA, for example, recently approved (2012) its first gene therapy product, Glybera, for lipoprotein lipase deficiency. The manufacturer, uniQure, plans its commercial rollout in the second half of this year.
China's SFDA approved its first gene therapy product on October 16, 2003. It awarded a drug license to a Chinese firm, Sibiono, for Gendicine, a recombinant p53 tumor suppressor gene with an adenovirus vector. Head and neck squamous cell carcinoma was its target indication. In November, 2005, SFDA approved Shanghai Sunway Biotech's Oncorine, a genetically altered type-5 adenovirus targeting tumor cells with dysfunctional p53 genes. Both were developed with substantial government support.
SFDA's actions were controversial because, in its haste to catch up with the West, it allowed a lower standard of approval. Gendicine's clinical trial, for example, involved only 135 patients. In addition, the approvals were granted based on the tumor regression rate induced by gene therapy, not the FDA standard of an improvement in patients' 5-year survival rate.
What has the uptake been like for Gendicine and Oncorine? Early domestic revenues were modest due to the relatively high price (~3800 yuan/US$610) and the lack of coverage by government insurance. Specific sales figures are sketchy, but Gendicine sales in 2006 were only ~$2M. Sales in the first half of 2007 were $1.5M followed by orders for $3.8M (16,000 vials) in response to a national forum to build awareness. Subsequent sales could not have been overly robust because Benda Pharmaceuticals (OTC:BPMA) acquired Sibiono in 2007 for only $7.7M cash plus stock. BPMA is an OTC pink sheet stock that obtained its U.S. listing through a reverse merger (PIPE (APO)) in 2006 by acquiring Applied Spectrum Technologies. How is Benda doing? The most recent trade was $.0007/share. This is all you need to know. I was unable to find any sales numbers for Oncorine. There is an SA article on these two companies published in 2008 if you desire additional information.
There are well over one hundred firms worldwide working on gene therapy products, from big pharma down to nano caps no one has heard of. A "gene therapy" search on clinicaltrials.gov yields 9891 total trials. Refining the search criteria to "interventional trials with results" pares the number down to 350. There is a tremendous amount of activity in the space albeit most early stage.
As a general rule, if you want to invest in a gene therapy play, restrict your watch list to those firms with a product in at least Phase III. A search for completed interventional PIII trials funded by industry on clinicaltrials.gov yields 77 such trials. This list represents a pool of potential investment candidates. As always, though, you should thoroughly research each target before considering any action.
The theory of introducing new cells into tissue to treat disease has been around for some time. There were a few crude attempts made as far back as the early 1800's, but the field earned its legitimacy in bone marrow transplantations in the early 1950's, when Professor Jean Dausset discovered HLA antigens. This paved the way for the first non-related bone marrow transplant in 1973. The first cord blood transplant occurred in 1988 followed by the development of the first embryonic cell lines in 1998. The controversial nature of embryonic cells stunted the field's progress until 2006 when Shinya Yamanaka from Kyoto University discovered how to generate induced pluripotent stem cells (iPSC's) from murine fibroblasts. The following year, researchers discovered how to produce iPSC's from adult human cells. This literally opened the floodgates for worldwide stem cell research.
Cell therapy can be divided into two broad classes, autologous and allogeneic. The former describes cells harvested from the patient, treated and/or expanded and then introduced back into the same patient. This is clearly personalized medicine. It is highly desirable because it avoids the problem of immunologic matching. The latter involves harvesting cells from a universal donor and then expanding them in a laboratory for large-scale use. This process is more technically challenging since large numbers of cells are needed. Strict quality control procedures are required to insure that the cells maintain their characterization profile and efficacy. They also must be able to withstand cryopreservation and revival since they must be available "off the shelf." This process is most suitable for mass commercialization.
Human stem cells can be divided into two broad groups, embryonic and adult (somatic). The therapeutic attractiveness of embryonic cells is their pluripotency. They can differentiate into most adult cell types. An added bonus is the fact that, by nature, they are allogeneic.
As I mentioned earlier, the controversy surrounding the use of embryonic stem cells has greatly constricted research, so a great deal of attention and effort has been focused on adult stem cells. These are multipotent which means that they can differentiate into several different types of cells. They are less versatile than embryonic stem cells, but versatile enough to be suitable for a variety of therapeutic applications.
Source: John Kyle Creason
There are three subgroups comprising the adult stem cell space. Neural stem cells can differentiate into nervous system cells. The most common ones are neurons, astrocytes and oligodendrocytes. Mesenchymal stem cells, derived from the mesoderm, can differentiate into bone cells, cartilage cells and fat cells. Hematopoietic stem cells, found in bone marrow, can differentiate into blood and lymphoid cells.
Here is a graphic of the hierarchy of stem cells:
Source: Public Image
When you compare this graphic to the one below, it is clear to see why researchers have been so enthusiastic about working with the embryonic variety:
Source: Public Image
Cell therapy offers hope for sufferers of a long list of heretofore-incurable diseases including ALS, Alzheimer's, Parkinson's, multiple sclerosis and many cancers.
Here is an excerpt from a Genetic Engineering & Biotechnology News article from November that discusses the current market environment for cell therapy products:
There are over 15 cell therapy products commercially distributed by companies in the U.S. including: Dermagraft, Osteocel, PureGen, BioDfactor, BioDfence, Provenge, Carticel, Epicel, Nucel, Appligraf, GINTUIT, Trinity, Grafix, DeNovoET, Prokera, and AmnioGraft.
As the only cell-based immune therapy, Provenge falls out of cellular therapy. Two stem cell products (HemaCord and Clinimmune) were recently granted a BLA by the FDA and are now being commercially distributed in the U.S. by the nonprofit entities that own these products.
There are many stem cell sector products commercially distributed by companies in select countries in Europe, including: MySkin, CryoCell, ReCell, Carticel, Epicel, MACI, ChrondroCelect, AlloStem, BioSeed-C, co.don chondrospheres, Epidex, EpiGraft, and Diabecell. Additionally there are two point-of-care devices (by Therakos and Cytori) commercially marketed in Europe for cell-based treatments.
There are a similar number of stem cell sector products commercially distributed and only available in other similarly regulated countries including: Cupistem (S. Korea), Heartcelligram (S. Korea), Cartistem (S. Korea), J-TEC Epidermis (Japan), J-TEC Cartilage (Japan), J-TEC Corneal Epithelium (Japan), Prochymal (Canada and NZ), and CureXcell (Israel).
This excludes products commercially distributed in countries such as China and India where currently the regulations for these products are less defined.
The cell therapy products distributed in the U.S. and Europe in total are expected to generate approximately $900M in revenues in 2012. Removing Provenge revenue, the bona fide stem cell sector is expected to generate in the range of $550M in 2012. Despite the relative small size of the sector, it is trending in the right direction as this is twice what the sector is estimated to have generated in 2010.
While no cell therapy products received regulatory approval between 2001 and 2009, the sector has had 8 such approvals in the past 36 months.
The article also contains a link to a list of late-stage cell therapy trials.
Another article by BioProcess International provides additional market information, albeit ~2 years old. Here is an excerpt:
Some 275 therapeutic companies with about 240 cell-based therapies are currently on the market or in some stage of clinical development. These therapies can be roughly broken down as follows: ~77 in phase 1, ~89 in phase 2, ~27 in phase 3, and ~44 are commercial (marketed in at least one country).
On the books, we are tracking what we believe is a fairly accurate total of 27 phase 3 or pivotal cell therapy industry-sponsored products in clinical trials: 15 autologous (58%), three allogeneic, three allogeneic-autologous combinations, three allogeneics with devices, one allogeneic with gene modification, one allogeneic-autologous combination with a drug, and one autologous with gene modification. About half those products are fresh in their final formulation (predominately the autologous ones). Seventeen of the 27 are being developed by companies based in the United States, with the remainder in Europe and Asia.
When you scrutinize that list for typical signs of commercial life, only 10 of those trials can be considered "active" by any measure. These can be broken down as follows: six autologous (58-60%), two allogeneic, one allogeneic with gene modification, and one allogeneic-autologous combination with a drug. Six of these are being developed by companies based in the United States.
Only 30-35% of currently marketed therapies (~13-16) have required and received regulatory approval. By contrast, we estimate that ~90% of therapies in development are "products" that will require premarket approval. Although ~70% of therapies currently marketed were not required to obtain regulatory approval when they were brought to market (and may still not now), this is not a statistical trend expected to continue. It is an artifact of a commercial environment that existed in a relative regulatory vacuum for these types of therapies - certainly a different regulatory framework from what now exists.
As far as investing opportunities go, I recommend focusing on those firms already commercializing products and/or those in at least in Phase III clinicals. A search on clinicaltrials.gov for completed PIII trials with results funded by industry yields 109. I am quite sure that every company has been profiled at some point on SA, so I will not re-list them here. As always, thorough research is mandatory before considering action.
On a final note on cell therapy, check out this video on the "skin gun." Most of the current marketed products are skin related. This one is truly impressive.
This field is defined by the use of cells, engineering and materials methods to repair or replace portions of or whole tissues. Consistent with the concept of personalized medicine, harvested autologous cells are grown in the laboratory in tightly controlled environments (typically on biologic scaffolds). Once a large number of cells are grown, they are reintroduced back into the patient. Numerous scaffolding materials have been experimented with (e.g., collagen, polyester) as part of structural research (e.g., bladders, blood vessels, heart valves). Theoretically, any organ or tissue can be manufactured ex vivo. Researchers have been attempting to grow human replacement parts for over 30 years.
Tissue engineering's credibility as a viable technology is largely attributable to one group, the Wake Forest Institute for Regenerative Medicine (WFIRM) in North Carolina. Its director, Dr. Anthony Atala, generated global attention beginning in 1998 when he and his research team successfully replaced malfunctioning bladders in seven patients with new ones grown in the laboratory. This was a stupendous proof of concept and energized the global effort to grow human replacement parts.
To date, Dr. Atala's team has grown 22 different tissues in the laboratory. They were the first to engineer functional blood vessels that were implanted into patients (2001), the first to engineer functional solid organ experimentally (miniature kidney that secretes urine)(2003), the first to engineer urine tubes that were implanted into patients (2004) and the first to engineer functional solid organs from recycled donor organs (miniature livers and penile erectile tissue)(2010).
WFIRM's progress has been truly extraordinary. Its pioneering work and impressive list of firsts have undoubtedly given many disease sufferers and injury victims hope that help may finally be on the way. When? Well, let's just say that patience will be required.
Looking a bit closer at WFIRM's progress to date, you can see that bladders and urine tubes (urethra repair) are the only cases where engineered tissue has been implanted into patients. The rest of its innovations remain experimental despite ~18 years of research. The pace of innovation going forward should accelerate, but it will undoubtedly be a long arduous endeavor before sophisticated fully functional full-size organs can be grown in the lab and implanted into patients. Unfortunately, time will be measured in decades instead of years. In some cases, heart and pancreas, for example, it is extremely doubtful that it will ever happen. From today's perspective, the organs' complexity is insurmountable.
Bladder tissue engineering, though, was a good initial candidate because this structure is relatively simple and it exhibits regenerative properties on its own. Dr. Atala is an urologist by training, so this further justified the choice. Here is the sequence of steps the researchers went through to engineer and replace the bladders:
1. Initial pre-biopsy exam of patient (urodynamic study, cystogram, genitourinary ultrasound, serum and urine analysis, 3D CT imaging of pelvic cavity (3 patients))
2. Bladder biopsy (1 cm2 sample)
3. Bacterial cultures performed on biopsy samples
4. Muscle cells scraped off the outer surface for culturing
5. Urothelial cells scraped off the inner surface for culturing
6. Both cell types cultured for 7 weeks in specialized incubators
7. Bladder scaffolds constructed (first 4 patients: decellularised bladder submucosa, 3 patients: biodegradable composite of collagen and PGA)
8. 70 plates of muscle cells seeded onto the outer surface of the scaffold
9. Growth medium added after 1 hour and changed every 12 hours
10. After 48 hours, 70 plates of urothelial cells seeded onto the inner surface of the scaffold
11. Growth medium added after one hour and changed every 12 hours
12. Seeded scaffolds placed in a sealed container and incubated for 3-4 days
13. Tissue sample obtained from seeded scaffolds for examination and confirmation of cellular attachment
14. Engineered bladders implanted
The total time from biopsy to implantation was ~8 weeks. It is clear to see that it is a technically demanding process requiring highly skilled highly trained personnel to execute. As such, it will remain in research institutions for a very long time. The cost to scale this kind of operation up in the private sector would be prohibitive. WFIRM has a staff of ~300 MD/PhD's, for example. They have capabilities that are unique in the world. It would take years to replicate what it is doing. This is a service business that cannot be shrink wrapped.
So where are the investment opportunities in tissue engineering? I do not see any right now because research institutions are doing almost all of the work. Some spinouts are inevitable but these are at least several years away from happening, in my view.
A "tissue engineering" search on clinicaltrials.gov yields 51 studies. Refining the search to Phase IIIs funded by industry yields a big goose egg. There is a long road ahead.
This area, along with in vitro meat, has had a fairly large dose of hype surrounding it. The most egregious fable is the potential to construct a new organ simply by pressing the "print" button. Here is one of my favorite graphics from explainingthefuture.com:
The ability to print a new heart or new pair of lungs by magically pressing a button will probably never happen in our lifetimes. The complexity of the task is way beyond what researchers can surmount. It is important to remember that the current state of the applied science is confined to relatively simple structures like bladders, urethras, tracheas, skin and blood vessels. It is also important to remember that, in an absolute sense, these structures are highly complex. It has taken decades for scientists to progress as far as they have.
A presentation that Dr. Atala gave a couple of years ago about printing a kidney illustrates the point. Listen carefully to his monologue. The purpose of his presentation is to "shock and awe" the audience. His salesmanship is understated but it is salesmanship. He states that the ability to print a fully functional kidney is years away even though he holds a prototype in his hand. Another interesting aspect of his show is the inclusion of one of his bladder replacement patients. This validates the concept of tissue engineering and lends credibility to the prospects of organ printing even though the latter is still highly experimental. Dr. Atala's efforts to build public awareness of regenerative medicine are laudable. It is important, though, to be realistic about what can be done today and what remains far in the distance.
The ability to print a new heart is even further away than the ability to print a kidney. Dr. Atala demonstrates pulsating cardiomyocytes in his presentations, but this is about as far as researchers have gotten. For example, there is a profound demand for an engineered "patch" of myocardium that could be used to repair/replace post-infarction scar tissue. The surface area of a viable patch would need to be 10-50 cm2 with a thickness of several millimeters. Scientists can produce tissue samples this large but they have had difficulty achieving a thickness beyond 100µm. Oxygen will not diffuse beyond this level without substantial vascularization. And even if they achieve this, the patch would still need to integrate instantaneously with the host tissue in order to survive and do so while withstanding relentless systolic pressure. To say that researchers need to be both persistent and patient is a profound understatement. I salute them.
The ability to print a fully functional heart is, sorry to say, a quantum leap beyond the humble patch. I hate to disappoint those of you who were about to bid adieu to your low-fat diet based on the hope of ordering a new ticker in a few years. Let's just say that I wouldn't dust off the deep fryer just yet.
The most realistic near-term opportunity for 3D Bioprinting is drug discovery. Three-dimensional constructs offer big pharma heretofore-unachievable human cellular response data to drug compounds. Up to now, animal studies and two dimensional cell cultures have been the best tools. In addition, the process can be automated and should be less expensive. For those of you following Organovo (ONVO), a collaboration agreement with a large pharmaceutical firm that includes a sizable investment in the company is the catalyst that you should watch for. regenHU, based in Zurich, is another bioprinter manufacturer to watch.
In Vitro Meat
This is where the hype has gotten the furthest ahead of reality. In vitro meat, or "shmeat" as some comedians have called it, is tissue engineering (cultured meat) for the gastronomically inclined. The capability of growing theoretically unlimited amounts of protein is profoundly appealing to all sorts of save-the-planet types. Many people apparently believe that this method of meat production will end global hunger, slow global warming and save countless animals' lives while providing us with a limitless source of leather. The website of Modern Meadow is a superb example of this hyperbole.
The concept of growing meat in a petri dish got its start in 1995 when the FDA approved NASA's techniques for doing it as a means of producing protein for long-term space travel.
Greens love the concept because of the high-perceived cost of producing meat for consumption. Animal farming takes up ~30% of the earth's surface and accounts for ~18% of greenhouse gas emissions, courtesy of methane-spewing cows. Saying it another way, cows are only ~15% efficient in producing meat from grain and other foods. According to Isha Datar, it takes 1.6 kg of feedstock and 3500 liters of water to produce one 8 oz. steak while emitting 4.5 kg of CO2.
PETA (People for the Ethical Treatment of Animals) got into the act in 1998 by offering $1M to the first laboratory that uses chicken cells to produce a commercially viable meat product. The original deadline was June 30, 2012 but it was extended to January 1, 2013. No winners were announced. No winners will ever be announced. The reason is the "commercially viable" requirement.
A harsh economic reality confronts the dreamers who believe that meat grown in a laboratory will be a viable source of protein in humankind's global food chain. Despite the low efficiency level of current meat-producing methods, market prices are typically ~$4/pound due to scale economies. It is big business. How does in vitro meat compare? According to Jason Matheny from the University of Maryland, a kg of in vitro beef will cost a cool $1M or ~$455,000/pound. Christina Agapakis discusses the fatal flaws of the meat-in-a-dish concept in greater depth in her April 24, 2012 article. I think that it will be awhile before we see in vitro meat in our local supermarkets.
Neuralstem: A Case Study in Patience
A Phase I clinical trial is the first stage in the formal regulatory approval process. Although investigators usually collect some pharmacokinetic data, the primary objective, or endpoint, is confirming that the initial conservative dose does no harm to the recipient. These trials usually involve a small group of patients, typically 10 - 30, depending on the product or procedure. The nature of Phase I trials normally preclude it from generating any enthusiasm from observers. It is just too preliminary. It is the first small step in a multiyear process. The road to eventual FDA approval is long, steep and filled with potholes.
Recently, though, one company's Phase I results garnered substantial attention. Neuralstem's (CUR) cell therapy procedure for ALS patients produced encouraging results. Its neural stem cells, NSI-566, appeared to interrupt the progression of the disease in a subgroup of fifteen subjects. The star, though, was patient #12, Ted Harada. His condition actually IMPROVED. This is unprecedented in the ALS universe. Mr. Harada subsequently relapsed a year later and received additional stem cell injections in the cervical area, but his initial response was truly extraordinary. The need for long-term immunosuppressant drugs appeared to be obviated as well.
NSI-566 gives ALS researchers a long-delayed sense of hope in their so-far futile attempt to arrest the progression on this pernicious disease. Today, there is only one FDA-approved drug for ALS, Sanofi's Rilutek (riluzole). Its claim is merely to delay the time before the patient has to go on a ventilator. The depressingly modest nature of Rilutek's claim exemplifies researchers' frustrating lack of progress.
So why has the market not reacted to this positive news by driving CUR's stock up? Its current market cap of $86M clearly contradicts the enormous upside potential of cell therapy. Why are institutional investors staying away? One reason is the substantial degree of uncertainty surrounding cell therapy's future, especially the potential for an SAE as trial doses escalate. The other issue depressing CUR's stock price is the extraordinary length of time remaining before any hope of an NDA. In my opinion, it will be a decade or more before any domestic commercialization will occur and easily five or more years before anything significant happens ex-U.S. (based on what we know today). It is going to be a long tough slog to FDA or EMA approval.
A review of the timeline of NSI-566's ALS Phase I trial illustrates the point. Broadly speaking, a Phase I usually takes ~9 - 12 months to complete. Here is CUR's ALS Phase I timeline:
12/08: IND filed.
9/2009: IND approved by FDA
1/2010: First patient dosed in lumbar region
11/2011: First patient dosed in cervical region
8/2012: Last patient dosed
2/2013: Projected end of trial (6-month follow up on last patient)
The formal trial period is ~3.5 years and over 4 years from the IND filing date. Phase II and III trials are, by definition, longer than Phase I's so you can see that there is no light at the end of the tunnel. Even the Phase II for ALS might not begin until 2014 due to the wait for FDA review and clearance of the Phase I results.
Regenerative medicine is truly one of the amazing developments in history. Our children and grandchildren will undoubtedly be able to benefit from a wide variety of innovative techniques to address serious disease and injury. Unfortunately for us, we are a bit too early for most of it.
In the investing realm, I suggest restricting your attention to the gene therapy firms. They are further along in their development cycle. Cell therapy companies are viable candidates for your long-term watch list because most of the products and procedures are only in Phase I clinicals. There is a long way to go. Tissue engineering currently resides in research institutions so just keeping abreast of developments is the best prescription.
At some point, though, to paraphrase Mr. Warhol, the gene and cell therapy companies will enjoy their 15 months of fame. They will be on Gartner's hype cycle graph to be sure. When? Who can say? I will be one who will keep an eye on things, though. I may even gamble on one or two of them when the timing is right.