When Someone Has to Spend Millions on Small Molecule Screening to Get Things Moving

There are any number of reasons why promising lines of research get stuck. Simple abandonment is a surprisingly common one; people outside the scientific community have little appreciation of the degree to which the floor of the forest is littered with valuable raw materials, just waiting for someone to spend the effort to forge them into useful goods. Many researchers have little interest in implementation, or fail to convince funding sources to continue their initial exploration, or the people involved move on, or the tools are hard to use and no-one else wants to make the effort to replicate the discoveries. It is sometimes amazing that anything is accomplished, watching the way in which most academic labs organize themselves.

Another common problem is the lack of suitable tools to manipulate a mechanism of interest, related to disease or aging. Once researchers find a mechanism, and have the means to probe its operation, the next step is to build ways to influence it. Some of the most common traditional tools are genetically engineered animal lineages, in which genes of interest are inserted or removed in the germline, gene therapies that increase or decrease protein levels in cells and adult animals, and small molecules that can increase or decrease protein levels, or interfere in or enhance protein interactions. Of those, only small molecules have traditionally resulted in clear path to clinical application, though gene therapies are starting to become more practical for those purposes.

What happens when researchers have an interesting mechanism, but don't have a small molecule that can manipulate that interesting mechanism? Well, they are stuck when it comes to moving closer to the clinic, unless they can raise a fairly sizable amount of funding for screening, as well as produce a sufficiently cheap screening methodology to allow a very large number of compounds from the standard libraries to be tested. The cost of a comprehensive screening exercise to find candidate small molecule drugs can be a few million dollars, which is why there are a sizable number of companies working on ways to reduce that cost and raise the odds of success. Expending these sizable resources offers no guarantee of finding a viable compound, or even a viable starting point. That is why many projects just stop right there, and remain halted until the slow grind of grant-writing and incremental discovery leads to a potential candidate compound in some other way.

In recent years, the new ability to cultivate arbitrary bacterial species from soil, rather than the tiny minority that has traditionally been the case, has unlocked the door for compound discovery relating to destruction of problem molecules. Every molecule in the human body can be consumed and broken down by at least one species of soil bacteria. Finding the tools that bacteria use for that purpose is low-cost and reliable in comparison to old-style screening from compound libraries: just grab a soil sample, separate the bacteria, drop in the protein that needs destruction, and see which of the bacteria thrive on that diet. A number of research groups have produced proof of principle results with modest budgets.

While that works just fine for targets such as the 7-ketocholesterol associated with atherosclerosis, as well as glucosepane cross-links, both of which are implicated in the aging process, and that we'd be far better off without, the approach doesn't work when the objective is to alter rather than destroy aspects of cellular metabolism. For example, it would be very useful to have drugs that interfere in the operation of alternative lengthening of telomeres (ALT), a mechanism that is only active in cancer cells. All cancers must lengthen their telomeres constantly in order to maintain rampant growth. If both ALT and telomerase-based telomere lengthening could be suppressed, then cancers would wither.

Work on finding ways to manipulate ALT is essentially stuck on the point that someone needs to spend a few million dollars in order to buy a chance at finding a candidate small molecule drug. No-one really wants to take that wager, and would much rather wait on incremental progress in the field to turn up a possible path forward. Perhaps that will happen in a year, perhaps not for twenty years, no-one can tell. It seems to me that for those areas of research blocked in this way, and where success would be very valuable, then paying for the screening would be a sensible act of high net worth philanthropy. For that to take place, however, it would require either a good understanding of the field on the part of more wealthy individuals, or a good packaging of the ideas involved on the part of a non-profit entity.

Comments

@Reason, are you sure that 7-ketocholesterol is part of lipofuscin?

Posted by: Ariel at December 13th, 2018 7:51 PM

@Ariel: Hmm. I was thinking they were associated, but that's probably because research programs are close together. I'm fairly certain oxidized lipids and lipofuscin go hand in hand, but you are probably right. I'll amend the text.

Posted by: Reason at December 13th, 2018 8:42 PM

Another problem with ALT is that we don't know which genes control it. I wonder why it's so difficult to find them.

Posted by: Antonio at December 14th, 2018 2:25 AM

How do we know that ALT is a single molecular process that can be interfered with by a single small molecule drug? It could be several independent molecular processes, and interfering with one via a small molecule drug may this have no effect.

Also the use of soil bacteria to find enzymes that can break down human proteins seems to my layperson knowledge to be - just feed a plot of bacteria that protein and see if they can survive. You can throw billions of bacterial enzymes at the proteins without needing to first identify all the enzymes. With ALT, the molecules behind the process have not yet been identified.

The bacterial enzymes would destroy the ALT molecules rather than interfere with them, but that could perhaps be a good starting point for then neutering them a bit so they only interfered.

The problem is - how to interface these two unknown sets of molecules?

Posted by: Jim at December 14th, 2018 2:25 AM

They are associated in some way, but we cannot say for now that 7KC is part of lipofuscin.

Posted by: Ariel at December 14th, 2018 12:15 PM

@Antonio, if we know ALT genes we can just break them using CRISPR or supress by RNA interference -- main problem is that we lack such info.

Posted by: Ariel at December 14th, 2018 12:18 PM

I agree with Jim and Antonio - without even understanding the basic mechanism for how ALT works it would be a big gamble to spend millions on a small molecule assay. That's not to say we can't learn anything from an assay.

Posted by: Mark at December 15th, 2018 11:09 AM

Hi there ! Just a 2 cents.

I am not sure that 7KC is part of lipofuscin, but it would not surprise me; lipofuscin is a strange mix, an amalgam of mostly oxidized PUFA lipids (DHA/EPA/ARA mainly), coming from the phosphatylcholine and phosphatylethanolamine largest phospholipids in the inner/outer mitochondrial membrane. Also, a sizeable amount of carbonylated proteins and oxidized macromolecules in it. While we know cholesterol is a large part of mitochondrial membranes for mitochondrial membrane fluidity/kinetic, I would not be surprised to see extra-cellular oxidized cholesterol end up extracellular milieu with lipofuscin, such as in the lysosomes where most lipofuscin clogs things and halts the autophagosome and proteasome. With it, yes, but as part of it/in it, not sure; like among the many debris and residue, possible.

In atherosclerosis (which I have), the main oxidizer is LDL (LDL-ox, oxidized LDL), people that had the least atherosclerosis at the most LDL-oxidize lag. Meaning, they had higher TAC/ORAC/Redox function that protected against LDL-ox ROS formation; LDL-ox is like this magnet for macrophage invasion and excess ROS production in the atherolscerotic lesion as the macrophagess trie to mop up the LDL. All this, is ROS inflammation and (v)LDL-ox main culprit. This is why it is crucial to reduce Total cholesterol and make sure to replace LDL for HDL specie through enzymatic conversion by liver-X stearoyl and cholesterol synthesis genes in liver reordering.

ALT is a combination of thing, it is recombination, SCE (Sister Chromatic Exchange), thus serious chromosomal reordering/chopping up and fusions (telomeric fusions), which are highly 'unstable' events of 'small uncapped' telomeres. Basically, the cancers have highjacked the telomeric machinery towards dysfunction to theri advantage; such as, POT1, Shelterin Complex, Ku67, TRF1, TRF2, all this no longer 'working correctly' as it should; and, at the epigenetic level, there will be changes for sure (mainly, in CpG rich islands which correlate to cancer arrival). Cancers are capable of deep chromosomal highjacking and hence, ALT. In ALT, it is more than just end termini telomeres of the chromosomes, it goes down to the centromere/sub-telomeres; like completely messing it up to extract telomeres and 'make new ones' 'from bits' here and there. That completely destabilizes the whole system and cancer can then take over without the need for telomerase. Telomerase is not a prerequisite to increase telomeres (this was demonstrated in certain studies where the telomeres lengthened without telomerase activation or without ALT); this means ALT is probably not the sole other means of telomere elongation possible. Some genes, some enzymes, have dual/redondant functions and can 'cover up' for a non-working one; like a 'back up' that is not as good as the original, but you know 'good enough' in the mean time that the original one gets back in order. We have this view that telomerase and ALT, are the Sole ones (there are still tons we don't know), maybe not; most likely, not.

Telomerase is their first choice because it greatly increases proliferation and it acts as a dual role; fitness improver (through lower ROS/increase telomeres, like in immune cells) and increased epigenetic aging element (via communication to epigenome DNA methyl clock).

I am not sure of it, because when we look at menopause or andropause, both show substantial loss of hormones (estrogen/testosterone), and with hormone therapy you boost telomerase levels and hormones levels; and stave off menopause/andropause...thus, what is the meaning of this - antogonistic pleiotropy. Telomerase is activated via estrogenic brain receptors (or testosterone to estrogen conversion), hence it improves 'fitness' in ailing older adults (frailty) by accelerated growth and muscle formation (mTOR/IGF). But, in the inverse, it accelerates epigenetic aging and cancers may hijack it (although you have more immune power from higher telomeres in immune cells to kill them; offset/compensation; but, telomerase, itself is a cancer enabler, but, more precisely, is a 'healthy aging' enabler). IN the sense, by having more estrogen/testosterone and stronger immune system, you fight off cancer and can live your full life - Healthy Aging/'Fit' Aging..but still aging - NOT reversal of aging or slowing of aging; slowing of 'health decline/illness/frailty'...yes. There is a difference.
And will die on clock - due to telomerase itself, in the epigenome.

Just a 2 cents.

Posted by: CANanonymity at December 15th, 2018 4:08 PM

Some in the field would argue that AI/ML will greatly alleviate the difficulty and expense of screening, faster than many realize. Insilico being a notable example, but far from alone. If this is right, then philanthropic funds could be better spent accelerating work and communication at the intersection of these fields.

Posted by: Karl Pfleger at December 16th, 2018 2:03 PM

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