We woke up to the twittering of birds in a tree just outside our room in Lake Powell Resort. I made a cup of coffee and stepped outside onto the balcony. The sun was lighting up the hills and the air had a warm dryness to it. Today we would be visiting Antelope Canyon and Horseshoe Bend. The weather was perfect for the visit.
We left Grand Canyon early the next day en route to Monument Valley. This was the main attraction for me. I grew up watching Hollywood movies. I still remember dialogs and scenes from these epics; John Wayne galloping across the three iconic buttes in Stagecoach, Clint Eastwood climbing the Totem Pole in Eiger Sanction and the title song “Old Turkey Buzzard” in MacKenna’s Gold, as the buzzard effortlessly zooms over the valley floor “waiting for something down below to die”. These scenes and many more were filmed in Monument Valley. And I could not wait to see the place where these still vividly remembered movies were shot.
The Grand Canyon, one of the seven natural wonders of the world, and Monument Valley, where countless Wild West movies were shot—these and nearby Bryce Canyon and Zion National Park were on my bucket list for a long, long time. I had been itching to see them but the Corona virus had thrown a monkey wrench into the plans. But with the vaccine, the tide was turning. People were beginning to travel and lead at least a semblance of their normal lives. I was ready to go!
Picture above depicts spiral forms found in developing systems throughout the universe. Left, the Pinwheel Galaxy 25 million light years from earth. Photo, the Hubble Consortium, NASA, ESA. Right, a conch shell on my table here on earth. Photo, Ranjan Mukherjee
Nature is elegant in its simplicity. There are a set of laws that explain her workings. They are simple, elegant and sometimes, used repeatedly. Consider the gravitational force between two bodies, first propounded by Newton. It is a force that varies inversely as the square of the distance (the inverse square law). Gravitation is a universal law, not because we have tested it everywhere in the universe (an impossibility) but because we have not seen any deviation anywhere yet. In fact, the trajectories of our spaceships and space probes are calculated largely based on these equations and they have held up so far with the space probe Voyager exploring right up to the cold wastes at the edge of our solar system. The inverse square law also explains another attractive force, the electrostatic force of attraction between two opposite, stationary charges (Coulomb’s law). These laws have withstood the test of time.
The same is true with life and its evolution. A useful paradigm like the genetic code is used throughout the animal kingdom. The four nucleotides that form a DNA molecule, the twenty amino acids that give rise to proteins are found in all bacteria, plants and animals. Evolution has selected for these and eliminated countless others. The eliminated ones are lost to history unless something turns up in the fossil record. When something so uniquely perfect is found, it makes sense to keep reusing the basic framework with subtle modifications to satisfy the specific needs. One example is the spiral forms seen in certain developing systems, inanimate or living, as gigantic and far flung as a faraway galaxy or as simple and down-to-earth as a growing sea shell (figure above). A second example, the main subject of this article, is The Fibroblast Growth Factor (FGF) family.
Consider how a multicellular organism grows from a single, fertilized egg. The single egg divides into two, then four, eight and so on. Soon the cells in the developing embryo begin to get organized into a particular pattern that heralds the shape of the adult to come. Regions like the limb bud begin to grow and then, after a fixed interval, stop growing. There must be signaling cues that instruct these cells where to grow, when to grow and when to stop. These cues are the growth factors. Fibroblast Growth Factors (FGFs) belong to this family of signaling proteins. They are extracellular signaling molecules that mediate a whole host of cellular processes; growth, proliferation, differentiation, angiogenesis, organogenesis, cell survival, epithelial repair and wound healing.
The first members, FGF1 and FGF2 were identified in the early 1970s. They induced proliferation of fibroblasts, hence the name: Fibroblast Growth Factors. At that time, they were called acidic FGF (aFGF) and basic FGF (bFGF) respectively, based on their isoelectric point. Unfortunately, the FGF name has stuck even though later members do not cause cell proliferation. Since then, 22 members of the mammalian FGF family have been identified based on sequence homology. They can be further sub-grouped according to their mode of action. Most of them act locally, either in a paracrine or autocrine manner. Notable examples of this subfamily are FGF1, FGF2, FGF7 and FGF10, to mention a few. These FGFs utilize heparin sulfate proteoglycans found on the cell surface and extracellular matrix as essential cofactors.
In contrast, three of the family members, FGF19, FGF21 and FGF23 are secreted directly into the bloodstream and act at distal sites in an endocrine manner. These do not utilize heparin sulfate but do require alpha or beta-klotho as essential cofactors. Recent studies including crystal structure analysis indicate these cofactors are essential to their mechanism of action.
The last group of FGFs (FGF11-FGF13), are not secreted and act intracellularly by modulating voltage gated ion channels.
The autocrine and endocrine FGFs mediate their activity by binding to and activating four FGF receptors (FGFR1 – FGFR4). These belong to another large family of transmembrane receptors, the receptor tyrosine kinases. Upon binding of the FGF ligand to the extracellular domain, there is a structural reorganization of the receptor dimer which induces phosphorylation at specific tyrosine residues in the intracellular domains. These, in turn, activate a number of signaling pathways depending on the ligand and cell type that lead to the dizzying list of activities mediated by the FGFs.
Perhaps, way back in time, such a signaling molecule and its cognate receptor evolved in a prehistoric life form. It proved versatile and useful. Nature is efficient. It reused the paradigm for other related purposes. The relevant genes were duplicated, random mutations were selected for by the inexorable forces of natural selection and soon several growth factors and kinase receptors appeared controlling the many different processes needed to grow and sustain a multi-cellular organism. Some examples are the Epidermal Growth Factors, Insulin and Insulin like Growth Factors, Vascular Endothelial Growth Factors and the Fibroblast Growth factors. The FGFs are the largest of this family with 22 members.
Recombinant FGF2 is used for the topical treatment of burns, skin grafts, recalcitrant skin ulcers, diabetic- gangrene and diabetes related ulcers in China. This is just one of the twenty two FGFs. Preclinical and clinical research are underway to find if the other members can be turned into useful drugs. In particular, the endocrine FGFs hold great promise. In preclinical studies, FGF21 has been shown to ameliorate diabetes, dyslipidemia, reduce body weight, liver fat and non-alcoholic steatohepatitis. If translated into the clinic, this could be a game changer in the treatment of many diseases associated with our modern lifestyle and abundance of high calorie, tasty foods and sugar-rich drinks. We look forward to more medicines from the FGF family.
Fourteen billion years ago the evolution of the present universe as we know it, began. It began with a Big Bang. At that infinitesimal point in time the universe was super tiny, super dense and super hot. Then suddenly, it exploded. Space began to expand and has been expanding ever since. Matter and energy that had remained compacted in a tiny, tiny dot, were suddenly and violently released and scattered across the entire universe in the form of a hot, charged plasma. With time the universe cooled. Particles of matter began to combine in different ways. The first atoms were formed. The simplest atom was hydrogen, the most abundant element in the universe followed by helium. Over time, these gases slowly condensed into gas clouds. In some regions a critical mass was reached. Inside the extremely dense, hot centers of these protostars, hydrogen nuclei began fusing to form helium releasing enormous amounts of energy in the process. The first stars were born. The firmament began to sparkle with starlight. In the high-energy inferno inside large stars, nucleosynthesis led to the formation of more complex elements including carbon, nitrogen, oxygen, phosphorus. The explosions of these large stars seeded the galaxies with the elements necessary for life. Heavier elements were formed during mergers of neutron stars or in exploding super-novae, spewing their contents across the entire cosmos. The gravity of large stars attracted matter that gradually coalesced and started revolving around them trapped in the stars’ gravitational fields. Planets were formed. One such star is our sun and one of the eight planets revolving around the sun is our beloved earth. It was formed 4.5 billion years ago.
Originally, the earth was an amorphous mass of hot, molten magma. Gradually it cooled. Water vapor that had been released from the hot rocks condensed and fell as rain. Oceans and land appeared. There were the elements; hydrogen, nitrogen, oxygen, phosphorus and, most importantly, carbon with its unique chemistry, all abundantly present in the universe, all crucial for the formation of life. These were concentrated in shallow pools at the edge of salty seas. As these pools dried in the hot sun, they became further concentrated. Their proximity and the warmth of the sun caused them to react with one another. Complex molecules arose; nucleotides, amino acids, sugars and fatty acids, the building blocks for nucleic acids, proteins, carbohydrates and lipids. The stage was set for a momentous happening. Dark, massed storm clouds thundered on the horizon. Lightning split the skies. Rain fell in torrents. Mightily the oceans heaved.
And then suddenly, about four billion years ago, from this soup of complex macromolecules, warmed by the sun and stirred by winds, life appeared on earth. At first it was a tiny, inconspicuous blob of protoplasm enclosed by a membrane protecting its precious contents. But it pulsated, grew and replicated itself by splitting into two equal halves, the two daughter cells. These cells, in turn, replicated, again and again. Life had appeared on earth and was off to the races. With time, cells began to utilize photosynthesis using the green pigment chlorophyll to harvest energy directly from the sun to synthesize simple sugars from water and carbon dioxide. These evolved into the green plants and trees we see today. Single cells clumped together to form multicellular organisms. In them, cells differentiated to become neurons, hepatocytes, adipocytes or myocytes giving rise to the organs; brain, liver, fat or muscle, each type very different from the other but each performing specific tasks for the good of the entire organism. Life evolved over a period of four billion years from the simple, single celled animalcule to the enormously complex, integrated life forms of today; the tiny mosquito, the gigantic blue whale, the spreading oak tree and the most intriguing of them all, modern man, Homo sapiens— Man the Wise, with a brain complex enough to contemplate the beginning of the universe and the origin of life. And he continues contemplating and probing, knowing that he is made from the dust of stars, one with the universe and evolving with it.
Featured image above depicts two colliding spiral galaxies. Photo: The Hubble Heritage Team, NASA,ESA